FIELD OF THE INVENTION
The present invention relates to two novel crystalline forms of Zofenopril calcium, to
processes for their preparation and their use in pharmaceutical compositions.
BACKGROUND OF THE INVENTION
Zofenopril calcium of formula I, chemically named (4S)-(2S)-3-benzoylthio-2-
methylpropionyl-4-(phenylthio)-L-proline calcium salt, is a non-peptidic orally active
sulphydryl ACE inhibitor with a long-lasting action and it is currently marketed for the
treatment of hypertension.

The manufacturing process for many pharmaceuticals is hindered by the fact that the
organic compound which is the active ingredient has handling difficulties during the
manufacturing process and may impart undesirable properties to the final drug or
dosage form. In addition it can be difficult to control the polymorphic form of the
active pharmaceutical ingredient throughout the manufacturing process.
For pharmaceuticals in which the active ingredient can exist in more than one
polymorphic form, it is particularly important to ensure that the manufacturing process
for the active ingredient affords a single polymorph with a consistent level of
polymorphic purity. If the process leads to a polymorph with varying degrees of
polymorphic purity and/or or where the process does not control polymorphic inter
conversion, serious problems in dissolution and/or bioavailability can result in the
finished pharmaceutical composition comprising the active ingredient.
2

Zofenopril calcium polymorphs are disclosed in patents US 6,515,012 and US 4,316,906.
The method for the preparation of Zofenopril calcium as disclosed in US 4,316,906 is
described in US 6,515,012 as comprising steps as follows:
a) Condensation between cis-4-phenylthio-L-proline and (D)-3-(benzoylthio)-2-
methylpropionyl chloride in aqueous solution keeping pH at values of 8-8.5 by
addition of 5N sodium hydroxide;
b) subsequent acidification with HCL, extraction with isobutyl acetate and
concentration of extracts, washing with saline solution, to give (4S)-1-[(2S-
3(benzoylthio)-2-methylpropinoyl]-4-phenylthio-L-proline;

c) Treatment of the resinous material, from the previous step, in isopropanol
solution with potassium 2-hethylhexanoate to obtain the corresponding
potassium salt;
d) Dissolution of the potassium salt in water to a 57 % concentration and very
slow addition, with simultaneous seeding, of a slight excess of a 2N calcium
chloride aqueous solution to precipitate the desired calcium salt. The resulting
product is washed thoroughly with water, dried under vacuum at comparatively
high temperature to give the desired calcium salt as dry powder; melting point
about 250° C. Alternatively:
e) (4S)-1 -[(2S-3(benzoylthio)-2-methylpropinoyl]-4-phenylthio-L-proline is
dissolved in ethanol and treated with the same volume of an aqueous
suspension containing one equivalent of CaO; after removing ethanol and
subsequently washing with ether, the aqueous suspension is freeze dried to
obtain the calcium salt with melting point 235-237°.
According to US 6,515,012 the synthesis described in US 4,316,906 (cited above at point a),
b) and c) mainly yields polymorph Form A, but also polymorph Form B in very variable
percentages and never below 20%. Moreover, the alternative synthesis described (at point d)
affords a partially amorphous product, with very variable characteristics in which Form A,
when present, is in concentrations much lower than those obtained in the preceding process.
US 6515012 B2 and US 6521760 Bl disclose a process for the preparation of substantially
pure polymorph Form A from Zofenopril calcium comprising the following steps:
3

a) Reaction of S-(-)-3-benzoylthio-2-methyl-propanoic acid chloride and cis-4-
phenylthio-L-proline in water at pH ranging from 9.0-9.5 and recovery of
zofenopril in its acidic form;
b) Salification of acid zofenopril with a potassium salt in alcoholic solution and
recovery of the resulting potassium salt;
c) Conversion of the potassium salt to the calcium salt by addition of an aqueous
solution of zofenopril potassium salt to a calcium chloride aqueous solution at
70-90°C with simultaneous seeding to promote the precipitation of polymorph
Form A.
However, the synthesis disclosed in the aforesaid US patents for the preparation of polymorph
Form A has the disadvantage that the reaction is carried out at a relatively high temperature
(80-85°C) at which inter conversion of the polymorphs is possible. Consequently, although
substantially pure Form A can be obtained from the above process, it is not very reliable and
the possibility of traces of Form B cannot be completely eliminated.
The aforesaid US patents also disclose a process for the preparation of polymorph Form B
comprising the following steps:
a) A solution of zofenopril potassium salt (0.27M) is sprayed in luke warm water (55°C),
while adding a calcium chloride solution, the solution is such that the total amount of
drug and calcium chloride are equimolar;
b) The resulting suspension containing the slurry product is heated at 85°C for 12-14 hrs
to obtain complete conversion to Form B;
c) After cooling at about 25°C, the product filtered, washed with water until it is
substantially free from chloride ions and then dried under vacuum.
WO 2007/003963 discloses a process for the preparation of substantially pure polymorph
Form C (monohydrate form) of Zofenopril calcium comprising the following steps:
a) Reaction of S-(-)-3-benzoylthio-2-methyl-propanoic acid chloride and cis-4-phenylthio-L-
proline in water at pH ranging from 9.0-9.5 and recovery of Zofenopril in its acidic form;
b) Salification of acid Zofenopril with a potassium salt in alcoholic solution and recovery of
the resulting potassium salt;
4

c) Conversion of the potassium salt to calcium by addition of an aqueous solution of calcium
chloride dihydrate to an aqueous solution of Zofenopril potassium salt at 50-55°C.
The polymorph Form C described in the aforesaid WO 2007/003963 patent application has
the advantage that it is prepared at milder conditions than the experimental conditions
reported for the polymorph A and B. In addition, it was found to be purer with respect to
contamination by other forms (polymorph Forms A and B), as indicated by XRPD data and
generally more stable to polymorphic inter conversion.
However, although, the properties of Form C and the processes to prepare it are generally
better and more convenient that those described for previous polymorphic forms, it has been
observed that under certain conditions during dosage form preparation, such as micronization
or wet granulation, the Form C product can exhibit very slight changes in polymorphic purity.
Although this difference was only to a very small extent, it could lead to variation in
dissolution profile and subsequent problems in the pharmaceutical composition development.
Although, formulation development may be able to circumvent the potential problems with
Form C, it was considered that an alternative polymorphic form with improved properties
over all the known polymorphic forms may make development and manufacture more
convenient and efficient and could also lead to improved pharmaceutical compositions.
OBJECT OF THE INVENTION
Therefore the object of the invention was to provide a new polymorphic form, of Zofenopril
calcium, which is convenient to manufacture, and has improved properties suitable for
formulation development and a marketed pharmaceutical composition.
SUMMARY OF THE INVENTION
The present inventors have surprisingly developed two new polymorphic forms of Zofenopril
calcium with improved properties which circumvent the problems associated the polymorphic
forms reported in the prior art as described above.
5

The new polymorphic forms of Zofenopril calcium have been designated as Form E and Form
F. Both Form E and Form F are crystalline anhydrous forms of Zofenopril calcium.
The present inventors have also developed convenient processes for the preparation of the
novel Forms E and F under mild conditions.
Therefore, in a first aspect of the present invention there is provided an anhydrous, non-
solvated crystalline Zofenopril calcium.
In a second aspect of the present invention there is provided Zofenopril calcium Form E
characterised by an XRPD spectrum comprising the following 29 peaks: 4.2, 4.8, 9.6, 17.5,
18.0, 19.3, 19.9, 20.6 and 24.4 ± 0.2 degrees 29.
Form E may be further characterized by a differential scanning calorimetry (DSC) with an
endothermic peak at about 255.2°C
In a third aspect of the present invention there is provided Zofenopril calcium Form F
characterised by an XRPD spectrum comprising the following 29 peaks: 4.6, 6.0, 8.3, 10.2,
14.5, 16.5, 17.1, 18.2, 19.9, 21.4 and 23.5 ± 0.2 degrees 29.
Form F may be further characterized by a differential scanning calorimetry (DSC) with an
endothermic peak at about 200.2°C.
In a fourth aspect of the present invention there is provided a process for preparing Zofenopril
calcium Form E comprising the steps of: a) dissolving a salt of zofenopril in a water miscible
organic solvent; b) mixing the solution obtained in step a) with an aqueous solution of a
calcium salt and c) isolating the Zofenopril calcium Form E, with the proviso that the salt of
zofenopril in step a) is not an amine salt.
Preferably, the water miscible organic solvent is an alcohol, an ether, a cyclic ether, a ketone
or an amide.
6

Preferably, the water miscible organic solvent is an alcohol, such as a straight chain, branched
or cyclic Ci to C6 alcohol. More preferably, the alcohol is selected from methanol, ethanol,
propanol, isopropanol, n-butanol or mixtures thereof.
Alternatively, the water miscible organic solvent is a cyclic ether, preferably selected from
tetrahydrofuran and dioxane or mixtures thereof.
Alternatively, the water miscible organic solvent is an amide, preferably selected from
dimethyl formamide, formamide and N, N-dimethyl acetamide or mixtures thereof.
Preferably, the Zofenopril salt in step a) is a metal salt, which is preferably selected from a
potassium, sodium, lithium, calcium, magnesium or aluminium salt. Most preferably, the
metal salt is a potassium salt.
Preferably, the calcium salt in step b) is selected from the fluoride, chloride, bromide, iodide,
oxide, hydroxide, carbonate, nitrate, sulfate or acetate salts.
Most preferably, the calcium salt is calcium chloride.
Preferably steps (a) and (b) are carried out at a mild temperature of up to 60°C.
In a fifth aspect of the present invention there is provided a process for preparing Zofenopril
calcium Form F comprising the steps of: a) dissolving an amine salt of Zofenopril in a water
miscible organic solvent; b) mixing the solution obtained in step a) with an aqueous solution
of a calcium salt and c) isolating the Zofenopril calcium Form F
Preferably, the amine salt of zofenopril is selected from the dicyclohexylamine,
cyclohexylamine, benzylamine, N-methylbenzylamine, or a-methylbenzylamine salts. Most
preferably, the amine salt is the dicyclohexylamine salt.
Preferably, the water miscible organic solvent is an alcohol, an ether, a cyclic ether, a ketone
or an amide.
7

Preferably, is an alcohol, more preferably a straight chain, branched or cyclic alcohol Ci to C6
alcohol. Preferably, the alcohol is selected from methanol, ethanol, propanol, isopropanol, n-
butanol or mixtures thereof.
Alternatively, the water miscible organic solvent is a cyclic ether, preferably selected from
tetrahydrofuran and dioxane or mixtures thereof.
Alternatively, the water miscible organic solvent is an amide, preferably selected selected
from dimethyl formamide, formamide and N,N-dimethyl acetamide or mixtures thereof.
Preferably, the calcium salt in step b) is selected from the fluoride, chloride, bromide, iodide,
oxide, hydroxide, carbonate, nitrate, sulfate or acetate salts.
Most preferably, the calcium salt is calcium chloride.
Preferably, steps (a) and (b) are carried out at a mild temperature of up to 60°C.
In a sixth aspect of the present invention there is provided a pharmaceutical composition,
comprising Zofenopril calcium Form E or Zofenopril calcium Form F.
Preferably, the pharmaceutical composition according to the sixth aspect of the present
invention is used to treat or prevent a disorder wherein inhibiting an angiotensin converting
enzyme (ACE) is beneficial. Preferably, the disorder is selected from hypertension, cardiac
decompensation, myocardial infarction, acute myocardial infarction, heart failure or chronic
heart failure.
In a seventh aspect of the present invention there is provided Zofenopril calcium Form E
comprising less than 10%, preferably less than 5%, preferably less than 1% and most
preferably less than 0.5% of Zofenopril calcium in other polymorphic forms.
In an eighth aspect of the present invention there is provided Zofenopril calcium Form F
comprising less than 10%, preferably less than 5%, preferably less than 1% and most
preferably less than 0.5% of Zofenopril calcium in other polymorphic forms.
8

BRIEF DESCRIPTION OF THE ACCOMPANYING FIGURES
Figure 1. X-ray powder diffraction (XRPD) of Zofenopril calcium Form E.
Figure 2. Differential scanning calorimetry (DSC) of Zofenopril calcium Form E.
Figure 3. Thermo gravimetric analysis (TGA) of Zofenopril calcium Form E.
Figure 4. X-ray powder diffraction (XRPD) of Zofenopril calcium Form F.
Figure 5. Differential scanning calorimetry (DSC) of Zofenopril calcium Form F.
Figure 6. Thermo gravimetric analysis (TGA) of Zofenopril calcium Form F.
DETAILED DESCRIPTION OF THE INVENTION
As outlined above, the present invention provides two new crystalline forms of Zofenopril
calcium, Form E and Form F, which are non-hygroscopic, polymorphically pure and stable
and have beneficial properties which avoid the problems associated with prior art forms.
The differences in XRPD data between the novel Forms E and F and prior art forms of
Zofenopril calcium are illustrated in Table 1.
Table 1: XRPD comparison [20 values]

Polymorph
A
(WO00/0798
4) Polymorph B
(WO00/07984) Polymorph C
(WO2007/0396
3) Polymorph E Polymorph
F
4.2
4.3
4.6
4.8 4.8
4.9 4.9
6.0
7.4
8.1
8.3
9

Polymorph
A
(WO00/0798
4) Polymorph B
(WO00/07984) Polymorph C
(WO2007/0396
3) Polymorph E Polymorph
F
8.7
9.1
9.6
9.9
10.1
10.2
10.8
11.7
12.2
13.0
13.7
14.5 14.5
14.8
15.6
16.0 16.0
16.5
17.1 17.1
17.5 17.5 17.5
18.0
18.2 18.2
18.5 18.5
18.7
19.0 19.0
19.3
19.4
19.9 19.9
20.0 20.0
10

Polymorph
A
(WO00/0798
4) Polymorph B
(WO00/07984) Polymorph C
(WO2007/0396
3) Polymorph E Polymorph
F
20.5 20.5 20.5
20.6
21.4 21.4
21.5
21.7
21.8 21.8
22.3
22.9
23.0
23.1
23.5 23.5
23.9
24.4
24.5
24.6 24.6
25.7
27.1
In addition convenient processes for the preparation of Forms E and F have been provided by
the present invention. These processes use mild conditions and low temperatures thus
minimizing the occurrence of polymorphic inter conversion and producing Forms E and F
with very high polymorphic purity.
Preferred embodiments of the processes according to the present invention are described
below.
A preferred process for the preparation of Zofenopril calcium Form E comprises: adding an
aqueous solution of calcium chloride dihydrate to a clear water miscible organic solvent
11

solution of Zofenopril potassium salt at 25-30°C. The resulting suspension is stirred for 4
hours. The suspension is filtered at 25-30°C and the product is washed by water until free
from chloride ions. The water miscible organic solvents can include alcohols (methanol,
ethanol, propanol, isopropanol, n-butanol), cyclic ethers (tetrahydrofuran, dioxane) and
amides (dimethylformamide, N,N-dimethylacetamide).
Preferably, the wet solids are dried under reduced pressure at 65°C until the moisture content
falls below 0.5%.
The XRPD pattern of the Form E product thus obtained is different from the reported
polymorph A, Polymorph B and Polymorph C of Zofenopril calcium as represented in the
Table 1.
Polymorph E is also obtained in the case of reverse addition in the first step when a clear
solution of Zofenopril potassium salt is added to a clear aqueous solution of calcium chloride
dihydrate.
The temperature employed in the process for the preparation of the novel crystalline Form E
of Zofenopril calcium is preferably from 20-60°C and more preferably from 25-30°C.
A preferred process for the preparation of Zofenopril calcium Form F comprises adding an
aqueous solution of calcium chloride dihydrate to a clear water miscible organic solvent
solution of Zofenopril dicyclohexylamine salt at 25-30°C. The resulting suspension is stirred
for 3 hours. The suspension is filtered at 25-30°C and the product is washed by water until
free from chloride ions. The water miscible organic solvents can include alcohols (methanol,
ethanol, propanol, isopropanol or n-butanol), cyclic ethers (tetrahydrofuran or dioxane) and
amides (dimethylformamide, formamide orN,N-dimefhylacetamide).
The wet solids are preferably dried under reduced pressure at 55°C until the moisture content
falls below 0.5%.
12

The product obtained, Form F, exhibited a characteristic XRPD pattern and was different
from the reported polymorph A, Polymorph B Polymorph C and Polymorph E of Zofenopril
calcium as represented in Table 1.
Polymorph F is also obtained in the case of reverse addition in the first step when a clear
solution of Zofenopril dicyclohexylamine salt is added to a clear aqueous solution of calcium
chloride dihydrate.
The temperature employed in the process for the preparation of the novel crystalline Form F
of Zofenopril calcium is preferably from 20-60°C and more preferably from 25-30°C.
In the processes according to the present invention, the reaction mixture is maintained at a
temperature of up to 60°C for 2 to 30 hours before filtering the suspension. Preferably, the
reaction mixture is maintained at a temperature of from 55 to 60°C for 2 to 4 hours before
filtering the suspension. Preferably, the reaction mixture is maintained at a temperature of
from 25 to 30°C for 30 hours before filtering the suspension.
Preferably, the two salt solutions are mixed at a temperature up to 60°C.
Preferably, the Zofenopril calcium isolated is washed with water, preferably until free from
chloride ions.
Preferably, the Zofenopril calcium isolated is dried, preferably under reduced pressure.
Preferably, the Zofenopril calcium is dried at a temperature up to 70°C.
Preferably, the Zofenopril calcium is dried until the moisture content falls below 1%,
preferably to below about 0.5%.
Preferably, the temperature throughout the whole process, according to the present invention
is kept at 70°C or less.
13

The major advantage of this invention is milder experimental temperature conditions of the
process to obtain the novel polymorphs and the polymorphic purity and stability of the Form
E and Form F. The polymorphic forms of the present invention also allow Zofenopril calcium
to be easily purified and obtained in very high chemical purity.
The pharmaceutical composition according to the sixth aspect of the present invention can be
a solution or a suspension but is preferably a solid oral dosage form. Preferred oral dosage
forms in accordance with the invention include tablets, capsules and the like which,
optionally, may be coated if desired. Tablets can be prepared by conventional techniques,
including direct compression, wet granulation and dry granulation. Capsules are generally
formed from a gelatine material and can include a conventionally prepared granulate of
excipients in accordance with the invention.
The pharmaceutical composition according to the present invention typically comprises one or
more conventional pharmaceutically acceptable excipient(s) selected from the group
comprising of a filler, a binder, a disintegrant, a lubricant and optionally further comprises at
least one excipient selected from colouring agents, adsorbents, surfactants, film formers and
plasticizers.
If the solid pharmaceutical formulation is in the form of coated tablets, the coating may be
prepared from at least one film-former such as hydroxypropyl methylcellulose, hydroxypropyl
cellulose or methacrylate polymers which optionally may contain at least from one plasticizer
such as polyethylene glycols, dibutyl sebacate, triethyl citrate, and other pharmaceutical
auxiliary substances conventional for film coatings, such as pigments and fillers.
Preferably, the pharmaceutical compositions according to the sixth aspect of the invention are
for use in treating and preventing disorders where inhibiting angiotensin converting enzyme
(ACE) is beneficial. Such disorders include, but are not limited to, hypertension, cardiac
decompensation, myocardial infarction, acute myocardial infarction, heart failure or chronic
heart failure.
14

Preferably the pharmaceutical compositions according to the present invention are in unit
dosage form comprising Zofenopril calcium in an amount of from 1 mg to 500 mg, such that
the amount of Zofenopril calcium administered is from 0.1 mg to 100 mg per Kg per day.
The details of the invention, its objects and advantages are illustrated below in greater detail
by non-limiting examples.
Examples
FormE
The preparation of crystalline Form E of Zofenopril calcium is illustrated in examples 1 to 4.
The products obtained exhibited identical data as depicted in Figures 1, 2 and 3.
Example 1
To a clear alcoholic (methanol, ethanol, propanol, isopropanol, n-butanol) solution of
Zofenopril potassium salt an aqueous solution of calcium chloride dihydrate is added at 25-
30°C and resulting suspension is stirred for 4 hrs. Then this suspension is filtered at 25-30°C
and the product is washed by water until free from chloride ions. The wet solids are dried
under reduced pressure at 60°C until the moisture content falls below 0.5%.
Example 2
To a clear aqueous solution of calcium chloride, an alcoholic (methanol, ethanol, propanol,
isopropanol, n-butanol) solution of Zofenopril potassium salt is added at 25-30°C.
Temperature of the reaction mixture is maintained for 4 hrs. Then this suspension is filtered at
25°C and the product is washed by water until free from chloride ions. The wet solids are
dried under reduced pressure at 60°C until the moisture content falls below 0.5%.
Example 3
To a clear alcoholic (methanol, ethanol, propanol, isopropanol, n-butanol) solution of
Zofenopril potassium salt an aqueous solution of calcium chloride dihydrate is added at 50-
55°C and resulting suspension is stirred for 4 hrs at 50-55°C.Then this suspension is filtered at
50-55°C and the product is washed by water until free from chloride ions. The wet solids are
dried under reduced pressure at 60°C until moisture content falls below 0.5%.
15

Example 4
To a clear aqueous solution of calcium chloride dihydrate, an alcoholic (methanol, ethanol,
propanol, isopropanol, n-butanol) solution of Zofenopril potassium salt is added at 50-55°C.
Temperature of the reaction mixture is maintained for 4 hrs at 50-55°C. Then this suspension
is filtered at 50-55°C and the product is washed by water until free from chloride ions. The
wet solids are dried under reduced pressure at 60°C until moisture content falls below 0.5%.
The same crystalline form of Zofenopril calcium (Form E) was obtained using cyclic ethers
(tetrahydrofuran, dioxane) and amides (dimethyl formamide, formamide, N,N-dimethyl
acetamide) as solvent.
FormF
The preparation of crystalline Form F of Zofenopril calcium is illustrated in examples 5 to 10.
The products obtained exhibited identical data as depicted in Figures 4, 5 and 6.
Example 5
To a clear alcoholic (methanol, ethanol, propanol, isopropanol, n-butanol) solution of
Zofenopril dicyclohexylamine salt, an aqueous solution of calcium chloride dihydrate is
added at 25-30°C and resulting suspension is stirred for 3 hrs (alcohol-water ratio 1:1). Then
this suspension is filtered at 25-30°C and the product is washed by water until free from
chloride ions. The wet solids are dried under reduced pressure at 55°C until the moisture
content falls below 0.5%.
Example 6
To a clear alcoholic (methanol, ethanol, propanol, isopropanol, n-butanol) solution of
Zofenopril dicyclohexylamine salt an aqueous solution of calcium chloride dihydrate is added
at 25-30°C and resulting suspension is stirred for three hrs (alcohol-water ratio 1:3). Then this
suspension is filtered at 25-30°C and the product is washed by water until free from chloride
ions. The wet solids are dried under reduced pressure at 55°C until the moisture content falls
below 0.5%.
16

Example 7
To a clear alcoholic (methanol, ethanol, propanol, isopropanol, n-butanol) solution of
Zofenopril dicyclohexylamine salt, an aqueous solution of calcium chloride dihydrate is
added at 50-55°C and resulting suspension is stirred for three hrs at 50-55°C (alcohol-water
ratio 1:1). Then this suspension is filtered at 25-30°C and the product is washed by water until
free from chloride ions. The wet solids are dried under reduced pressure at 55°C until the
moisture content falls below 0.5%.
Example 8
To a clear aqueous solution of calcium chloride dihydrate, an alcoholic (methanol, ethanol,
propanol, isopropanol, n-butanol) solution of Zofenopril dicyclohexylamine salt is added at
25-30°C and resulting suspension is stirred for three hrs (alcohol-water ratio 1:1). Then this
suspension is filtered at 25-30°C and the product is washed by water until free from chloride
ions. The wet solids are dried under reduced pressure at 55°C until the moisture content falls
below 0.5%.
Example 9
To a clear aqueous solution of calcium chloride dihydrate, an alcoholic (methanol, ethanol,
propanol, isopropanol, n-butanol) solution of Zofenopril dicyclohexylamine salt is added at
25-30°C and resulting suspension is stirred for 3 hrs (alcohol-water ratio 1:3). Then this
suspension is filtered at 25-30°C and the product is washed by water until free from chloride
ions. The wet solids are dried under reduced pressure at 55°C until the moisture content falls
below 0.5%.
Example 10
To a clear aqueous solution of calcium chloride dihydrate, an alcoholic (methanol, ethanol,
propanol, isopropanol, n-butanol) solution of Zofenopril dicyclohexylamine salt is added at
50-55°C and resulting suspension is stirred for three hrs at 50-55°C (alcohol-water ratio 1:1).
Then this suspension is filtered at 50-55°C and the product is washed by water until free from
chloride ions. The wet solids are dried under reduced pressure at 55°C until the moisture
content falls below 0.5%.
17

The same crystalline Form F of Zofenopril calcium was obtained using cyclic ethers
(tetrahydrofuran, dioxane) and amides (dimethyl formamide, formamide, N,N-dimethyl
acetamide) as solvent.
Stability studies of Polymorph E towards possible mechanical stress induced during dosage
form preparation
The following studies illustrate the stability of the polymorphic forms, according the present
invention, to the mechanical stress that occurs during dosage formation by wet granulation
method.
• Polymorph E when subjected to mechanical stress during particle size reduction (milling
using multimill) retained its polymorphic composition as depicted by thermal data
(XRPD, DSC and TGA). This showed that the form E is stable to mechanical stress to
which the API would be subjected during dosage form (tablet) preparation.
• Stability of Polymorph E was further studied by preparing its slurry in water (10% w/v)
and exposing this to 50-55°C for six hours. Thermal data (XRPD, DSC and TGA)
recorded after this exposure indicated no change in Polymorph E. These results suggested
that the polymorph E should be stable to wet granulation.
• In another stress study, the pallet of Polymorph E was prepared using Infra red
spectrophotometer press machine (pressure exerted -10 Tons). The thermal data (XRPD,
DSC and TGA) of this pallet was identical to that of before compression. This study also
showed stability of form E towards mechanical stress.
Similar results were seen when stress studies were conducted on Form F.
18

We claim:
1. An anhydrous, non-solvated crystalline Zofenopril calcium.
2. Zofenopril calcium Form E characterised by an XRPD spectrum comprising the following
29 peaks: 4.2, 4.8, 9.6, 17.5, 18.0, 19.3, 19.9, 20.6 and 24.4 ± 0.2 degrees 20.
3. Form E according to claim 2 characterized by a differential scanning calorimetry (DSC)
with an endothermic peak at about 255.2°C
4. Zofenopril calcium Form F characterised by an XRPD spectrum comprising the following
29 peaks: 4.6, 6.0, 8.3, 10.2, 14.5, 16.5, 17.1, 18.2, 19.9, 21.4 and 23.5 ± 0.2 degrees 29.
5. Form F according to claim 4 characterized by a differential scanning calorimetry (DSC)
with an endothermic peak at about 200.2°C.
6. A process for preparing Zofenopril calcium Form E comprising the steps of: a) dissolving
a salt of zofenopril in a water miscible organic solvent; b) mixing the solution obtained in
step a) with an aqueous solution of a calcium salt and c) isolating the Zofenopril calcium
Form E, with the proviso that the salt of zofenopril in step a) is not an amine salt.
7. A process according to claim 6, wherein the water miscible organic solvent is an alcohol,
an ether, a cyclic ether, a ketone or an amide.
8. A process according to claim 7, wherein the water miscible organic solvent is an alcohol.
9. A process according to claim 8, wherein the alcohol is a straight chain, branched or cyclic
Ci to C6 alcohol.
10. A process according to claim 9, wherein the alcohol is selected from methanol, ethanol,
propanol, isopropanol, n-butanol or mixtures thereof.
11. A process according to claim 7, wherein the water miscible organic solvent is a cyclic
ether.
12. A process according to claim 11, wherein the cyclic ether is selected from tetrahydrofuran
and dioxane or mixtures thereof.
13. A process according to claim 7, wherein the water miscible organic solvent is an amide.
14. A process according to claim 13, wherein the amide is selected from dimethyl formamide,
formamide and N, N-dimethyl acetamide or mixtures thereof.
15. A process according to any one of claims 6 to 14 wherein the Zofenopril salt in step a) is a
metal salt.
16. A process according to claim 15 wherein the metal salt is a potassium, sodium, lithium,
calcium, magnesium or aluminium salt.
19

17. A process according to claim 16 wherein the metal salt is a potassium salt.
18. A process according to any one of claims 6 to 17 wherein the calcium salt in step b) is
selected from the fluoride, chloride, bromide, iodide, oxide, hydroxide, carbonate, nitrate,
sulfate or acetate salts.
19. A process according to claim 18, wherein the calcium salt is calcium chloride.
20. A process according to any one of claims 6 to 19, wherein steps (a) and (b) are carried out
at a temperature of up to 60°C.
21. A process for preparing Zofenopril calcium Form F comprising the steps of: a) dissolving
an amine salt of Zofenopril in a water miscible organic solvent; b) mixing the solution
obtained in step a) with an aqueous solution of a calcium salt and c) isolating the
Zofenopril calcium Form F
22. A process according to claim 21 wherein the amine salt of zofenopril is selected from the
dicyclohexylamine, cyclohexylamine, benzylamine, n-methyl benzylmine, or a-methyl
benzylamine salts.
23. A process according to claim 22 wherein the amine salt is the dicyclohexylamine salt.
24. A process according to any one of claims 21 to 23, wherein the water miscible organic
solvent is an alcohol, an ether, a cyclic ether, a ketone or an amide.
25. A process according to claim 24, wherein the water miscible organic solvent is an alcohol.
26. A process according to claim 25, wherein the alcohol is a straight chain, branched or
cyclic alcohol Ci to C6 alcohol.
27. A process according to claim 26, wherein the alcohol is selected from methanol, ethanol,
propanol, isopropanol, n-butanol or mixtures thereof.
28. A process according to claim 24, wherein the water miscible organic solvent is a cyclic
ether.
29. A process according to claim 28, wherein the cyclic ether is selected from tetrahydrofuran
and dioxane or mixtures thereof.
30. A process according to claim 24, wherein the water miscible organic solvent is an amide.
31. A process according to claim 30, wherein the amide is selected from dimethyl formamide,
formamide and N, N-dimethyl acetamide or mixtures thereof.
32. A process according to any one of claims 21 to 31 wherein the calcium salt in step b) is
selected from the fluoride, chloride, bromide, iodide, oxide, hydroxide, carbonate, nitrate,
sulfate or acetate salts.
20

33. A process according to claim 32, wherein the calcium salt is calcium chloride.
34. A process according to any one of claims 21 to 33, wherein steps (a) and (b) are carried
out at a temperature of up to 60°C.
35. A pharmaceutical composition, comprising Zofenopril calcium Form E or Zofenopril
calcium Form F.
36. A pharmaceutical composition according to claim 35 for use to treat or prevent a disorder
wherein inhibiting an angiotensin converting enzyme (ACE) is beneficial.
37. A pharmaceutical composition according to claim 36 wherein the disorder is selected from
hypertension, cardiac decompensation, myocardial infarction, acute myocardial infarction,
heart failure or chronic heart failure.
38. Zofenopril calcium Form E comprising less than 10% of Zofenopril calcium in other
polymorphic forms.
39. Zofenopril calcium Form E comprising less than 5% of Zofenopril calcium in other
polymorphic forms.
40. Zofenopril calcium Form E comprising less than 1% of Zofenopril calcium in other
polymorphic forms.
41. Zofenopril calcium Form E comprising less than 0.5% of Zofenopril calcium in other
polymorphic forms.
42. Zofenopril calcium Form F comprising less than 10% of Zofenopril calcium in other
polymorphic forms.
43. Zofenopril calcium Form F comprising less than 5% of Zofenopril calcium in other
polymorphic forms.
44. Zofenopril calcium Form F comprising less than 1% of Zofenopril calcium in other
polymorphic forms.
45. Zofenopril calcium Form F comprising less than 0.5% of Zofenopril calcium in other
polymorphic forms.

Dated this 27th day of February 2008
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An anhydrous, non-solvated crystalline Zofenopril calcium