Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-06-08
2003-07-29
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S007200
Reexamination Certificate
active
06599886
ABSTRACT:
The present invention relates to clarithromycin (see Merck Index, 12
th
edition (1996), page 2404) of formula I, a well known and useful antibacterial agent:
A compound of formula I may be prepared in anhydrous form by known methods which typically require recrystallization of the crude product using various organic solvents or mixtures thereof for purification. A purified compound of formula I may be obtained in anhydrous form, e.g. with a water content of lower than 2%, e.g. clarithromycin crystal form II.
It has now surprisingly been found that a compound of formula I in pure form may be obtained from an aqueous medium in anhydrous form and in the form of a hydrate.
Thus in one aspect the invention provides a process for the production of a compound of formula I which comprises the steps of
(i) producing a solution of compound of formula I in the form of a salt in a solvent,
(ii) adjusting the pH, and
(iii) isolating a compound of formula I,
characterised in that the solvent in step (i) is an aqueous solvent medium which is selected from water or a mixture of water and organic solvent.
Advantages of the process include:
(i) elimination of large amounts of organic solvents according to the present invention in comparison with prior art processes, and
(ii) reducing the content of organic solvent in a compound of formula I, and
(iii) the process according to the present invention may be carried out on technical sale.
A process according to the present invention may be carried out as follows:
A compound of formula I, e.g. in crude form, as obtained in a production process, in the form of a salt, e.g. a salt with an acid, e.g. an acid as described below, may be dissolved in an aqueous solvent medium, or a compound of formula I in free form may be dissolved by addition of an acid, e.g. an organic acid, for example formic acid or acetic acid, or an inorganic acid, for example a hydrochloric, hydrobromic, nitric or sulphuric acid, preferably hydrochloric acid or sulphuric acid, to form in situ a salt with the dimethylamino group in 3′position of the sugar radical attached to the ring system in position 5. An aqueous solvent medium includes water or a mixture of water with one or more organic solvents, for example water miscible and water immiscible organic solvents, such as alcohols, e.g. methanol, ethanol or isopropanol; ketones such as acetone or methyl isobutyl ketone; alkyl esters such as of formic or acetic acid, e.g. methyl acetate, ethyl acetate, isopropyl acetate and butyl acetate; aromatic hydrocarbons such as toluene or xylenes, ethers such as tetrahydrofuran or methyl t-butyl ether; chlorinated hydrocarbons such as methylene chloride and amides such as monoalkyl and dialkyl amides, e.g. N-methylformamide, dimethylacetamide and dimethylformamide, preferably water or a mixture of water with alcohols, ketones and aromatic hydrocarbons, e.g. water or water containing 0.5 to 20% v/v, such as 1 to 15% v/v, organic solvent. An aqueous medium may, beside water, comprise one or more individual organic solvents, e.g. as described above. Appropriate reaction conditions for the production of a compound of formula I in the form of a salt according to the present invention may include, e.g.
(i) a temperature range of about −15° C. up to the reflux temperature of the solvent system present, such as from −10° C. to 50° C., e.g. from −5° C. to 40° C.;
(ii) an appropriate pressure, e.g. atmospheric pressure, and a pressure which is above or below atmospheric pressure; and
(iii) appropriate dilution, e.g. a dilution range between 1 g and 500 g of a starting compound of the formula I per liter of aqueous medium.
A resulting solution of a compound of formula I in the form of a salt in an aqueous solvent medium may be filtered, e.g. after charcoal treatment, to remove impurities and the pH of a filtered solution obtained may be adjusted to an appropiate value, e.g. by addition of a base. Suitable bases include, for example, an inorganic base, such as, for example ammonia or an alkali, e.g. sodium, potassium; earth alkali, e.g. calcium, magnesium; and ammonium; hydroxide, carbonate, bicarbonate; and an organic base, such as an amine, e.g. an alkyl amine, or a mixture of individual bases, e.g. as described above. A base may be preferably a hydroxide, e.g. sodium or ammonia; preferably in aqueous solution. The term “appropriate pH” includes a pH range wherein the compound of formula I is present in solution or suspension in the form of a free base. An appropriate pH value includes, e.g. about 7.0 to 10.0, such as 7.5 to 9.5, for example 8.0 to 9.0. A compound of formula I may precipitate and may be isolated, e.g. by a method as conventional, e.g. by centrifugation or filtration, and dried, for example at a temperature of about 30 to 100° C. to provide a compound of formula I in pure form, e.g. having a low organic solvent content.
A compound of formula I may be obtained in the form of a hydrate or in anhydrous form depending on the reaction conditions, drying conditions, and on the type and amount of solvent used:
(A) If in the production of a compound of formula I exclusively water is used as the aqueous medium, a compound of formula I in the form of a stable hydrate may be obtained having
(I) a water content of about 9 to 12%, such as about 9.5 to 11.5%, e.g. 10.0 to 11.0%, e.g. 10.7 to 10.8%, if the process temperature is a temperature higher than 24° C., such as 25 to 50° C., e.g. 30 to 40° C. or
(II) a water content of 5.5 to 8%, e.g. 6 to 7%, if the process temperature is lower than 25° C., such as 15 to 24° C., e.g. 20 to 24° C.
A compound of formula I in the form of a hydrate having a water content of 9 to 12% may be crystalline. The differential scanning calorimetry of a compound of formula I in the form of a hydrate having a water content of 9 to 12% may show at a heating rate of 10° C./min an endotherm, i.e. loss of water, between room temperature and 90° C.; an exothermic transition, i.e. related to a phase transition, at about 127 to 140° C.; and an endothermic peak at 224.6° C., i.e. because of melting of a compound of formula I in the form of a hydrate having a water content of 9 to 12%. Thermal gravimetric analysis at a heating rate of 5° C./minute may show a 9.2% weight loss between room temperature and 85° C. X-ray powder diffraction patterns of a compound of formula I in the form of a hydrate having a water content of 9 to 12% are given in Table 1 and more detailed in Table 2.
TABLE 1
d(A)
I/I
0
8.8
62
8.4
37
7.2
34
6.5
31
6.3
100
5.9
42
TABLE 2
d(A)
I/I
0
9.3
20
8.8
62
8.4
37
7.2
34
6.5
31
6.3
100
5.9
42
5.4
22
4.9
25
4.8
29
4.2
25
4.1
23
In Tables 1 and 2 “d” denotes the interplanar spacing; I/I
0
denotes the relative intensity and A denotes Angstrom.
A compound of formula I in the form of a hydrate having a water content of 5.5 to 8% may be crystalline. X-ray powder diffraction patterns of a compound of formula I in the form of a hydrate having a water content of 5.5 to 8% are given in Table 3 and more detailed in Table 4.
TABLE 3
d(A)
I/I
0
8.2
30
7.5
100
4.7
35
TABLE 4
d(A)
I/I
0
11.5
20
8.2
30
7.5
100
5.7
27
4.8
20
4.7
35
In Tables 3 and 4 “d” denotes the interplanar spacing; I/I
0
denotes the relative intensity and A denotes Angstrom.
Thus in another aspect the present invention provides a compound of formula I in the form of a hydrate having a water content of 9 to 12%, for example in crystalline form, e.g. having a X-ray powder diffraction pattern of Table 1, or e.g. Table 2.
In another aspect the present invention provides a compound of formula I in the form of a hydrate having a water content of 5.5 to 8.0%, for example in crystalline form, e.g. having a X-ray powder diffraction pattern of Table 3, or e.g. Table 4.
(B) If in the production of a compound of formula I a mixture of water and an alcohol, e.g. methanol, ethanol or isopropanol, in a ratio of 6:1 to 15:1, such as e.g. 8:1 to 10:1, e.g. 9:1 is used as the aqueous medium, a compound of formula I in the form of a stable hydrate may be obtained having a water content of 5.5 to 8%,
Centellas Victor
Diago Jose
Biochemie S.A.
Peselev Elli
Pfeiffer Hesna J.
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