DE20321227U1 - New isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A useful for treating e.g. bacterial and protozoal infections - Google Patents

Abstract

An isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A is new and has the monoclinic space group, average unit cell parameters as given in the specification. An isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of formula (I) is new and has the monoclinic space group, average unit cell parameters as given in the specification. [Image] S 1an organic solvent which is at least partially miscible with water; x : 1, 1.25, 1.5 or 2; y : 0, 0.5 or 1. An independent claim is also included for preparation of (I). ACTIVITY : Antibacterial; Protozoacide; Antiinflammatory. No biological data given. MECHANISM OF ACTION : None given.

Description

Under U.S.C. Section 119 (e) this application claims the priority of the prior provisional application No. 60 / 394,705, filed July 8, 2002, and earlier US Provisional Application No. 601393612, filed on July 3, 2002, the entire contents of which are hereby incorporated by reference are included.

Under 35 U.S.C. Section 119 claims this application priority prior to March 18, 2002 filed in Croatian Patent Application No. P20020231A.

FIELD OF THE INVENTION

The This invention relates to novel isostructural pseudopolymorphs of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A and pharmaceutical formulations comprising these.

BACKGROUND OF THE INVENTION

9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A is the first and still the only 15-membered semi-synthetic macrolide antibiotic on the market in the azalide group [Merck Index, 12th ed (1996), p. 157 (946)]. It has the formula

The Synthesis of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A. in U.S. Patent No. 4,517,359. Its antibacterial Spectrum (J. Antimicrob. Chemother., 1987, 19, 275), its mode of action (Antimicrob Ag Chemoth., 1987, 31, 1939) and pharmacology (Antimicrob J. Chemother., 1993, 31, Suppl.E, 1-198) are well known.

9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A occurs in amorphous form and in several different crystalline ones Forms due to different arrangements of the atoms in the crystal structure Marked are. Most of the forms are crystalline, being their crystal unit cells in addition to 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A contain different numbers of water molecules and / or solvent molecules (Pseudopolymorphs).

In U.S. Patent No. 4,517,359 is anhydrous amorphous 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A described with a melting point of 113 to 115 ° C. It can through Evaporation of the solvent from a chloroform solution of crude 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A. become. It is noncrystalline, but instead an amorphous one Product that resembles a solid frothy mass. In laboratory scale can a pure product either by chromatography of the crude end product or by dissolving of crude crystalline 9-deoxo-9a-aza-9a-methyl-9α-homoerythromycin A monohydrate or dihydrate in an organic solvent and subsequent Evaporation of the solvent to be obtained. Thus, pure amorphous anhydrous 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A will be obtained. This method is not for large-scale Production suitable.

The preparation of various amorphous, crystalline, solvated and hydrated forms of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A has already been described in the patent literature. See for example US 4,474,768 ; US 6,245,903 ; EP 1 103 558 ; CN 1 093370 ; CN 1 161971 ; WO 99/58541; WO 00/32203; WO 01/00640; WO 02/09640; WO 02/10144; WO 02/15842; WO 02/10181 and WO 02/42315. The materials thus produced are subject to various disadvantages including lack of purity, instability, hygroscopicity and the like.

Non-hygroscopic 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate was prepared as early as the mid-1980s by neutralization of an acidic solution of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A in one Acetone-water mixture produced. Its crystal structure (single crystal) was evaluated by recrystallization from ether and was characterized by the orthorhombic space group P 2 ₁ 2 ₁ 2 ₁ . The unit cell parameters, namely, the crystal axes a = 17.860 Å, b = 16.889 Å, and c = 14.752 Å, and the angles between the crystal axes, α = β = γ = 90 °, were reported at the 1987 Meeting of Chemists of Croatia (Book of Abstracts). Meeting of Chemists of Croatia, Feb. 19-20, 1987, p. 29). Thereafter, its crystal structure and preparation have been described in detail (J. Chem. Res. (S), 1988, 152, Ibid., Miniprint 1988, 1239, obtained June 4, 1987; Cambridge Crystallographic Data Base: GEGJAD).

Then was 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate in the US patent. No. 6,268,489. This patent disclosed the preparation of the dihydrate by crystallization from tetrahydrofuran and hexane with the addition of water. The product thus formed is crystalline and can be large scale be obtained in pure form. Its production, however, is subject several disadvantages with the use of water immiscible toxic organic solvents and the need for careful control of drying related to it.

Further techniques for the preparation of the dihydrate have already been described in the patent literature, eg in US Pat US 5,869,629 ; EP 0 941 999 ; EP 1 103 558 ; HR P 921491; WO 01/49697; and WO 01/87912. Various of the procedures described include precipitation of the dihydrate by recrystallization from water-miscible solvents by addition of water. However, the products formed by these and other methods described in the literature suffer from a number of distinct disadvantages associated with the necessary treatment of pharmaceutically pure 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A Materials to yield, purity and homogeneity of the products themselves. In fact, the products formed by the various prior art processes comprise varying amounts of combined and adsorbed solvents and water, thus imparting non-reproducible stability, purity, release and efficacy characteristics when incorporated into pharmaceutical formulations.

one of the objects The present invention provides a number of new isostructural pseudopolymorphs of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A with established crystal structures used in pharmaceutical formulations because of such structures more reproducible predictable Provide properties.

SUMMARY OF THE INVENTION

wobei
S ein organisches Lösungsmittel ist, das mindestens teilweise mit Wasser mischbar ist,
x 1, 1,25, 1,5 oder 2 ist,
y 0, 0,5 oder 1 ist,
wobei die Pseudopolymorphe durch die monokline Raumgruppe P 2₁ und einen Bereich von Einheitszellenparametern von
Kristallachsenlängen von a = 15,5–17,0 Å, b = 15,5–17,0 Å und c = 17,5–19,5 Å,
und
Winkeln zwischen den Kristallachsen von α = γ = 90° und β = 106–112°
gekennzeichnet sind.The invention relates to novel isostructural pseudopolymorphs of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of the formula I.

in which
S is an organic solvent that is at least partially miscible with water,
x is 1, 1.25, 1.5 or 2,
y is 0, 0.5 or 1,
where the pseudopolymorphs are represented by the monoclinic space group P 2 ₁ and a range of unit cell parameters of
Crystal axis lengths of a = 15.5-17.0 Å, b = 15.5-17.0 Å and c = 17.5-19.5 Å,
and
Angles between the crystal axes of α = γ = 90 ° and β = 106-112 °
Marked are.

The isostructural pseudopolymorphs thereof include the individual crystal units identified as compounds Ia-Im in Table 1 below, whose crystal packing is described in U.S. Pat 2 - 14 of the drawings is explained in the appendix. As explained, these are compounds having a unique crystal packing with a discrete channel formation in their unit cells (see FIG. 15 ). As a result of the channel formation, water and / or solvent molecules can be fitted into its cavities and dried to provide isostructural solid state forms, ie the pseudopolymorphs of the invention having the unique crystal structures such as their monoclinic space group P 2 ₁ and the lengths of their crystal axes and intervening Angles of their unit cells are indicated to be removed.

It is textbook knowledge that generally hydrates and / or solvates a Any connection can be defined as a fixed state forms Those who, except for the core linkage, should use water of crystallization and / or solvent molecules in the must have asymmetric unit of the crystal unit cell. Further have to these hydrated and / or solvated molecules in one stoichiometric relationship are determined to be the core interconnection and are thereby clearly distinguishable from adsorbed water and / or solvent molecules.

X-ray crystallography is the only method that should be used as an analytically clear and valid characterization of such hydrates and / or solvates. Various thermal methods (eg TGA or DSC) together with water and / or solvent content determinations (eg Karl Fischer water content determination or GC) can only be used as a supplement to the X-ray crystallographic data and can give false and speculative results. In addition, various literature data show that even a specific hydrate and / or solvate form can crystallize in different and distinct crystal units, ie in distinct pseudopolymorphs. By way of illustration, a known antibiotic, nitrofurantoin, crystallizes in two distinct monohydrate solid state forms with exactly the same water content (C ₈ H ₆ N ₄ O ₅ .H ₂ O), but with distinct crystallographic data, namely that monohydrate I crystallizes in the monoclinic space group P 2 ₁ / n while monohydrate II crystallizes in the orthorhombic space group P bca (EW Pienaar, M. Caira, Lotter AP, J. Crystallogr Spectrosc Res 23 (1993) 739-744, CSDB codes HAXBUD and HAXBUD01 ).

isostructural solid state forms, e.g. Pseudopolymorphs, can be very similar or even identical Have powder diffraction pattern. That is why the definite and unique identification of any isostructural solid State forms, e.g. of pseudopolymorphs, by single-crystal X-ray diffraction respectively.

According to the invention were the special crystal structures of a group of stable isostructural pseudopolymorphs of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A determines, of which at least one of the pseudopolymorphs in comparison with the previously described forms of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A a number of superior Features. In particular, a polymorph according to the invention, the isostructural 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorph of general formula I, where x = 1, y = 0, in comparison with the currently commercially available form of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, namely the dihydrate hereinbefore mentioned, a number of superior ones Properties on. Thus, this pseudopolymorph, in contrast to the dihydrate, among a wide range of preparative Conditions are produced reproducibly. Second, it can directly from the native solution crude 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A or crude 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A itself instead of a purified 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A material can be produced. Third, this new pseudopolymorph manufactured in high purity and in pharmaceutically acceptable quality become.

Fourth, the new pseudopolymorph is an air-stable, free-flowing form of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (based on the grainy appearance of its small crystals, see 16 ). Fifth, the new pseudopolymorph has significantly better dissolution rates in both acidic and neutral media compared to the dihydrate. Sixth, the natural dissolution rate (IDR) of the pseudopolymorph is much higher than the dissolution rate of the dihydrate. Seventh, the novel pseudopolymorph can be used in the preparation of a variety of pharmaceutical formulations intended for immediate controlled or sustained release applications. Finally, this new pseudopolymorph may be due to its extraordinary In contrast to the dihydrate or other previously known forms of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dissolution characteristics in the production of fast-acting oral and local, in particular topical, pharmaceutical formulations are successfully used.

• (a) Auflösen eines 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A-Materials in (1) einem organischen Lösungsmittel, das mindestens teilweise wassermischbar ist, (2) einem Gemisch solcher organischer Lösungsmittel, (3) einem Gemisch des organischen Lösungsmittels und Wasser oder (4) einem Gemisch von Wasser und mindestens einer mineralischen oder organischen Säure;
• (b) Kristallisieren des isostrukturellen Pseudopolymorphs aus der Lösung;
• (c) Isolieren des isostrukturellen Pseudopolymorphs; und
• (d) Überführen des isostrukturellen Pseudopolymorphs in ein stabiles isostrukturelles Pseudopolymorph der Formel I, wobei x = 1 und y = 0.

The present invention is based on a process for the preparation of the novel isostructural 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorphs of the formula I, the process comprising:

• (a) dissolving a 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A material in (1) an organic solvent which is at least partially water-miscible, (2) a mixture of such organic solvents, (3) a Mixture of the organic solvent and water; or (4) a mixture of water and at least one mineral or organic acid;
• (b) crystallizing the isostructural pseudopolymorph from the solution;
• (c) isolating the isostructural pseudopolymorph; and
• (d) converting the isostructural pseudopolymorph into a stable isostructural pseudopolymorph of formula I, where x = 1 and y = 0.

Finally, concerns the present invention also pharmaceutical formulations, the the new isostructural pseudopolymorphs of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A in combination with one or more pharmaceutically acceptable carriers and other excipients. The invention also allows a procedure for the treatment of bacterial and protozoan Infections and inflammatory Diseases in humans or animals exposed to them, this is the administration of such pharmaceutical formulations the individuals in need of such treatment.

BRIEF DESCRIPTION OF THE DRAWINGS

1 Figure 3 is a crystal packing diagram of the currently commercially available 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate (the structure encoded by GEGJAD described in the Cambridge Crystallographic database);

2 Figure 4 is a crystal packing diagram of an isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of Formula I (Compound Ia: x = 1, y = 0);

3 Figure 3 is a crystal packing diagram of another isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of the invention (Compound Ib: s = methanol, x = 1.25, y = 1);

4 Figure 3 is a crystal packing diagram of another isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of the invention (Compound Ic: S = ethanol, x = 1, y = 0.5);

5 Figure 3 is a crystal packing diagram of another isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of the invention (Compound Id: S = n-propanol; x = 1, y = 0.5);

6 Figure 3 is a crystal packing diagram of another isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of the invention (Compound Ie: S = isopropanol, x = 1.5, y = 0.5);

7 Figure 3 is a crystal packing diagram of another isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of the invention (compound If: S = n-butanol; x = 1.5, y = 0.5);

8th Figure 3 is a crystal packing diagram of another isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of the present invention (Compound Ig: S = isobutanol; x = 1.25, y = 0.5);

9 Figure 3 is a crystal packing diagram of another isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of the invention (Compound Ih: S = 1,2-ethanediol; x = 1, y = 0.5);

10 Figure 3 is a crystal packing diagram of another isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of the invention (Compound Ii: S = 1,3-propanediol; x = 1, y = 0.5);

11 Figure 3 is a crystal packing diagram of another isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of the invention (compound Ij: S = glycerol; x = 1, y = 0.5);

12 Figure 3 is a crystal packing diagram of another isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of the invention (Compound Ik: S = glycerol; x = 1.5, y = 0.5);

13 Figure 3 is a crystal packing diagram of another isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of the invention (compound II: S = acetone; x = 1, y = 0.5);

14 Figure 3 is a crystal packing diagram of another isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of the invention (Compound Im: S = dimethylsulfoxide (DMSO); x = 1, y = 0.5);

15 FIG. 4 is an illustration of a channel formation within the unit cell of the isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of general formula I.

16 is an SEM of the surface of the isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of the formula I (Compound Ia: x = 1, y = 0);

17 Figure 3 is a graph comparing the dissolution rates of the pseudopolymorph of the present invention and the known 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate at pH 3 and 37 ° C;

18 Figure 4 is a graph comparing the dissolution rates of the pseudopolymorph of the present invention and the known 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate at pH 6 and 37 ° C;

19 Figure 3 is a graph showing the solid state stability of the isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of Formula I (Compound Ia: x = 1, y = 0) under various loading conditions (temperatures of 30 to 70 ° C and humidities of 5 to 75% RH) explained.

20 Figure 9 is a graph showing the plasma profile of the pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of Formula I (Compound Ia: x = 1, y = 0) and of 9-deoxo-9a-aza -9a-methyl-9a-homoerythromycin dihydrate in rats after administration per os (50 mg / kg body weight).

21 Figure 4 is a graph showing the whole blood profile of the pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of Formula I (Compound Ia: x = 1, y = 0) and 9-deoxo-9a-aza -9a-methyl-9a-homoerythromycin dihydrate in rats after administration per os (50 mg / kg body weight).

22 Figure 4 is a graph comparing the dissolution rates of the pseudopolymorph Ik of the present invention and the known 9-deoxo-9a-aza-9a-methyl-9a homoerythromycin A dihydrate at pH 6 and 37 ° C.

DETAILED DESCRIPTION OF THE INVENTION

As used herein with reference to the isostructural pseudopolymorphs of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of the present invention, the term "substantially pure" refers to the pseudopolymorph of formula I represented by the monoclinic space group P 2 ₁ and the aforementioned average unit cell parameter is at least 90% pure. More specifically, the term "at least 90% pure" refers to the pseudopolymorphs of the invention containing no more than 10% of another compound, especially not more than 10% of another crystalline or amorphous form of 9-deoxo-9a-aza-9a. methyl 9a homoerythromycin A included. Preferably, the "substantially pure" pseudopolymorph of the invention is "substantially pure," ie, it contains 5% or less of another compound or crystalline or amorphous form of 9-deo xo-9a-aza-9a-methyl-9a-homoerythromycin A.

In addition, as used herein, the term "9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A material", which is used in step (a) the method of forming the isostructural pseudopolymorphs of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of these is any form of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, including crude or purified 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A or a solvate or hydrate thereof, either in crystalline or amorphous form; or to the "native Solution "of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A while of the last step of its syntheses (e.g., 9-deoxo-9a-aza-9a-homoerythromycin A ("9a-DeMet") as one of his last intermediate stages) is formed.

As As used herein, the term "crude 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A "9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A having a purity below the pharmaceutically acceptable purity, including from the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin obtained before its final purification A, include.

As As used herein, the term refers to native solutions of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A "on solutions from 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A in water or organic solvents or mixtures thereof, in the final step of the production of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A from its final intermediates (e.g., 9a-DeMet), prior to isolation crude 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A can be used.

9-Deoxo-9a-aza-9a-homoerythromycin A ("9a-DeMet"), which is used as a starting material in the processes claimed herein, is also known in the art as 11-aza-10-deoxo-10-dihydroerythromycin A ( 10-Dihydro-10-deoxo-11-azaerythromycin A) ( US 4,328,334 ; J. Chem. Res. (M) 1988, 1239). It is known and, for example, by conventional methods (see US 4,328,334 ; J. Chem. Soc., Perkin Trans. / 1986, 1881).

Solvents used in the native solutions of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A can include water, chlorinated solvents, eg, haloalkanes having one or two carbon atoms, such as chloroform or dichloromethane; Esters of acetic acid having a C ₂ -C ₄ lower alkyl group such as ethyl acetate, isopropyl acetate or n-butyl acetate; monobasic C ₂ -C ₄ alkanols such as isopropanol or 2-butanol; C ₁ -C ₄ ketones, such as acetone or isobutyl ketone; or aromatic or substituted aromatic solvents such as toluene.

1. Preparation of the pseudopolymorphs according to the invention

Step (a) - Dissolve the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A material

As disclosed above, becomes the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A material in step (a) of the process for producing the isostructural according to the invention Pseudopolymorphs in (1) an organic solvent containing at least z.T. is water miscible, (2) a mixture of such organic solvents (3) a mixture of the organic solvent and water or (4) a mixture of water and at least one mineral or organic acid solved. Organic solvents, thus suitable include lower aliphatic straight chain or branched alkanols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, sec-butanol, tert-butanol or allyl alcohol; cycloalkanols, such as cyclopentanol or cyclohexanol; Arylalkanols, such as benzyl alcohol; Diols such as 1,2-ethanediol, 1,2-propanediol, 1,3-propanediol, 1,4-butanediol or 2-buten-1,4-diol; Triols, such as glycerin; Ethers, such as diethyl ether, monoglyme, diglyme or 1,4-dioxane; Ketones such as acetone, 2-butanone; Esters, such as methyl formate, ethyl formate, Methyl acetate, ethyl acetate, or ethyl lactate; Amines, such as N-methylmorpholine, Amides, such as dimethylformamide or dimethylacetamide; Lactams, like 2-pyrrolidone, N-methylpyrrolidone; Ureas, such as N, N, N ', N'-tetramethylurea; Nitriles, such as acetonitrile or propionitrile; Sulfoxides, such as dimethylsulfoxide; or sulphone, like sulfolan.

The mineral or organic acids, to acidify can be used that in step (a) of the method of forming the pseudopolymorphs thereof can be used any usual mineral or organic acid include. Suitable examples include, but are not limited to, Hydrochloric acid, Sulfuric acid, sulphurous acid, Phosphoric acid, Carbonic acid, Formic acid, acetic acid, propionic acid, citric acid, tartaric acid, maleic acid, oxalic acid, chloroacetic acid, benzoic acid, methanesulfonic acid or p-toluene sulfonic acid.

The resolution of the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A material in step (a) is at temperatures from about 0 ° C to about 100 ° C, preferably at about 0 to about 80 ° C and especially desirable at Temperatures of about 5 to about 60 ° C performed.

Step (b) - crystallization the pseudopolymorph

The new isostructural invention Pseudopolymorphs are prepared from the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A solution in Step (b) of the method hereof either by controlled Cooling down, isothermal saturation the solution with water until a slight cloudiness the solution occurs, or by neutralization of the acidic solution with a common crystallized inorganic or organic base.

inorganic Bases that can be used that way include the usual ones inorganic bases, such as the hydroxides, oxides or carbonates of Groups I or II of the Periodic Table of the Elements, e.g. the alkali metal or alkaline earth metal bases, such as lithium, sodium, potassium, barium, Magnesium or calcium hydroxide; Sodium, magnesium or calcium oxide; Sodium- or potassium carbonate; Ammonia solutions. Organic bases which are thus suitable include organic amines, such as trimethylamine, triethylamine, piperidine, 3-methylpyridine, piperazine, Triethanolamine or ethylenediamine; or quaternary organic hydroxides such as tetramethyl-, Tetraethyl or tetrabutylammonium hydroxide.

The Crystallization can be carried out with or without seed crystal, i.e. by adding small amounts of one of the pseudopolymorphs of the invention in amounts of about 0.1 to about 5.0%, based on the amount of treated 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A starting material.

The Crystallization, whether by controlled cooling, isothermal saturation or neutralization of the acidic solution performed with base, is at temperatures of about -10 up to about 80 ° C, preferably from about 0 ° C up to about 40 ° C and especially desirable at temperatures of about 5 to about 25 ° C performed. The crystallization is completed in a period of about 30 minutes to about 7 days.

Step (c) - Isolation the isostructural pseudopolymorph

The crystalline isostructural pseudopolymorphs thereof are described in Step (c) in a conventional manner, e.g. Centrifugation, filtration or the like, work under reduced, atmospheric or under increased Pressure isolated. Subsequently the isolated pseudopolymorphs become water-miscible organic solvents (such as those described herein above) or in one such solvent, mixed with water, washed. Subsequently, the resulting Intermediate to conventional Way e.g. by fluid bed drying, Working under atmospheric Pressure at temperatures of about 20 to about 120 ° C or under reduced pressures of from about 2 to about 80 kPa and at temperatures of about 30 to about Dried 120 ° C.

Step (d) - Transferring the isotructural pseudopolymorphs in a stable isostructural Pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, Formula I, where x = 1 and y = 0

Finally will the transfer of the crystalline dried (or wet) isostructural pseudopolymorph of formula I, which was formed in step (b), into the pseudopolymorph Ia (x = 1, y = 0) by removal of the solvent and excess water by lyophilization or by drying under reduced pressures of about 0.01 to about 80 kPa or at atmospheric pressure and temperatures of about -100 to about 120 ° C carried out.

The novel isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of the general formula I, wherein x = 1, y = 0, which has been prepared by the process according to the invention in at least substantial purity, has fluctuating humidity conditions a good flowability, a porous crystal structure (see 16 ) and excellent stability characteristics (see 19 ) on. The improved properties of this pseudopolymorph relative to the commercially available 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate are disclosed in more detail in Examples 25 to 27 below.

2. Formulations of Pseudopolymorphs according to the invention

The novel 9-deoxo-9a-aza-9a-methyl-9a-homoetythromycin A pseudopolymorphs according to the invention can in the production of fast, controlled and delayed release pharmaceutical formulations used for oral, rectal, parenteral, transdermal, buccal, nasal, sublingual, subcutaneous or intravenous Administration are suitable. Such formulations can be used for Treatment of bacterial or protozoan infections in humans and animals as well as other conditions, such as inflammatory Diseases, be suitable.

Preferably The formulations are administered orally in the form of fast or controlled releasing tablets, microparticles, minitablets, capsules and oral solutions or suspensions or powders for the preparation thereof. additionally to the new isostructural invention 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorphs as an active substance the oral preparations optionally various pharmaceutical standard carrier and -excipients, such as Binders, fillers, Buffers, lubricants, lubricants, disintegrators, odorants, sweeteners surfactants Agents and coatings. Some Excipients can take several roles in the formulations, e.g. although Binders act as a disintegrating agent.

Examples for pharmaceutical compatible Disintegration aids for oral formulations which are suitable according to the invention comprise, but are not limited on, strength, pregelled starch, sodium, Sodium carboxymethylcellulose, croscaramellose sodium, microcrystalline Cellulose, alginates, resins, surfactants, effervescent Preparations, aqueous Aluminosilicates and cross-linked polyvinylpyrrolidone.

Examples for pharmaceutical compatible Binder for which include oral formulations which are useful herein but not limited on, acacia gum; Cellulose derivatives, such as methylcellulose, carboxymethylcellulose, Hydroxypropylmethylcellulose, hydroxypropylcellulose or hydroxyethylcellulose; Gelatin, glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, Sorbitol, starch, pregelled starch, Tragacanth, xanthan gum, alginates, magnesium aluminosilicate, polyethylene glycol or bentonite.

Examples for pharmaceutical compatible fillers for oral Formulations include, but are not limited to, Lactose, anhydrolactose, lactose monohydrate, sucrose, dextrose, Mannitol, sorbitol, starch, Cellulose (especially microcrystalline cellulose), dihydro- or Anhydro-calcium phosphate, Calcium carbonate and calcium sulfate.

Examples for pharmaceutical compatible Lubricants suitable in the formulations according to the invention are, but are not limited to, magnesium stearate, Talc, polyethylene glycol, polymers of ethylene oxide, sodium lauryl sulfate, Magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine and colloidal silica.

Examples for suitable pharmaceutically acceptable Odorants for oral formulations include, but are not limited to, synthetic flavors and natural aromatic oils, like extracts of oils, flowers, fruits and combinations thereof. Preference is given to vanilla and fruit aroma, including Banana, apple, sour cherry, peach and similar flavors. Your application depends on many factors, the most important of which is organoleptic acceptance the group of individuals occupying the pharmaceutical formulations.

Examples for suitable pharmaceutically acceptable Dyes for oral formulations include, but are not limited to, synthetic and natural Dyes, such as titanium dioxide, β-carotene and extracts of grapefruit peel.

Examples for pharmaceutical compatible coatings for oral Formulations that are typically for ease of swallowing, Modification of release properties, improvement of appearance and / or Masking the taste of the formulations used include, but are not limited on, hydroxypropylmethylcellulose, hydroxypropylcellulose and acrylate-methacrylate copolymers.

suitable examples for pharmaceutically acceptable sweeteners for oral Formulations include, but are not limited to, Aspartame, saccharin, saccharin sodium, sodium cyclamate, xylitol, mannitol, sorbitol, Lactose and sucrose.

suitable examples for pharmaceutically acceptable Buffers include, but are not limited to, citric acid, sodium citrate, Sodium bicarbonate, dibasic sodium phosphate, magnesium oxide, calcium carbonate and magnesium hydroxide.

suitable examples for pharmaceutically acceptable surfactants Agents include, but are not limited to, sodium lauryl sulfate and polysorbates.

The Formulations of the isostructural invention 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorphs can also intravenously or intraperitoneally by infusion or injection. Dispersions can also in a liquid carrier or mediators such as glycerin, liquid polyethylene glycols, triacetin oils and mixtures of which are produced. To improve the storage stability, such Preparations also contain a preservative to growth of microorganisms to prevent.

The pharmaceutical formulations for injection or infusion are suitable in the form of a sterile aqueous Solution, a dispersion or in the form of a sterile powder, containing the active substance, and, if necessary, for the preparation of such sterile ones solutions or dispersions suitable for infusion or injection, designed. these can optionally encapsulated in liposomes. In all make the final preparation must be sterile, liquid and under the conditions of and storage conditions to be stable.

Of the liquid carrier or mediator can be a solvent or a liquid one Dispersion medium, for example, water, ethanol, a Polyol (e.g., glycerin, propylene glycol, or the like), vegetable oils, not contains toxic glycerol esters and suitable mixtures thereof. A suitable flowability can by administration of liposomes, administration of a suitable Particle size in the case of dispersions or by the addition of surfactants become. The prevention of the action of microorganisms can by Addition of various antibacterial and antifungal agents, e.g. Paraben, chlorobutanol or sorbic acid. In many make are isotonic substances, e.g. Sugar, buffer and sodium chloride, recommended to adjust the osmotic pressure corresponding to that in the body fluids, especially in the blood, to ensure. One extended Absorption of such injectable mixtures can be achieved by introduction of absorption delaying Agents, such as aluminum monostearate or gelatin, can be achieved.

sterile injectable solutions can by mixing the isostructural 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorphs with a suitable solvent or one or several of the aforementioned excipients and subsequent sterile filtration getting produced. In the case of sterile powders for use in the preparation of sterile injectable solutions, include preferred Production process drying in vacuo and lyophilization, the powdery mixtures of isostructural pseudopolymorphs and the desired Excipients for later Production of sterile solutions supplies.

The Compounds of the invention can also for the production of locally acting topical formulations be used. Such formulations may also be other pharmaceutical contain acceptable excipients, like polymers, oils, liquid Carrier, surfactants Agents, buffers, preservatives, stabilizers, antioxidants, Moisturizers, emollients, colorants and odorants.

Examples for pharmaceutical compatible Polymers for such topical formulations are suitable, but include not limited on, acrylic polymers; Cellulose derivatives, such as carboxymethylcellulose sodium, Methyl cellulose or hydroxypropyl cellulose; natural polymers, such as alginates, Tragacanth, pectin, xanthan and cytosan.

Examples for suitable pharmaceutically acceptable oils which are thus suitable, include, but are not limited to, mineral oils, Silicone oils; fatty acids, Alcohols and glycols.

Examples for suitable pharmaceutically acceptable liquid carrier include, but are not limited to, water, alcohols or Glycols, such as ethanol, isopropanol, propylene glycol, hexylene glycol, Glycerol and polyethylene glycol or mixtures thereof in which the Pseudopolymorph solved or dispersed, optionally with the addition of non-toxic, anionic, cationic or nonionic surfactants, and inorganic or organic buffers.

Suitable examples of pharmaceutically acceptable preservatives include, but are not limited to not limited to various antibacterial and antifungal agents, such as solvents, for example, ethanol, propylene glycol, benzyl alcohol, chlorobutanol, quaternary ammonium salts, and parabens (such as methylparaben, ethylparaben, propylparaben, etc.).

suitable examples for pharmaceutically acceptable Stabilizers and antioxidants include, but are not limited to, ethylenediaminetetraacetic (EDTA), thiourea, tocopherol and butylhydroxyanisole.

suitable examples for pharmaceutically acceptable Moisturizers include, but are not limited to, Glycerin, sorbitol, urea and polyethylene glycol.

suitable examples for pharmaceutically acceptable Emollients include, but are not limited to, mineral oils, isopropyl myristate and isopropyl palmitate.

The Use of dyes and odorants in the topical according to the invention Formulations depends Of many factors, of which the most important are the organoleptic compatibility across from the group of individuals using the pharmaceutical formulations, is.

The therapeutically acceptable Amount of administered isostructural 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin according to the invention A pseudopolymorph varies depending on the compound chosen, the route of administration, the conditions of treatment, age and the status of the patient or animal species and is subject to the final Decision of the doctor, chemist or veterinarian, the course supervised the treatment.

suitable oral and parenteral doses can within the range of about 1 to about 200 mg per kg of body weight per day, preferably from about 5 to about 100 mg per kg of body weight and more preferably from about 5 to about 50 mg per kg of body weight vary per day. The 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorphs can be formulated in the form of a single dose ranging from about 1 to about 3000 mg, preferably from about 100 to about 200 mg and more he wishes from about 150 to about 600 mg of the active ingredient per dosage unit varied.

EXAMPLES

The isostructural according to the invention Pseudopolymorphs were prepared as described in Examples 1-22 below, using 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A in different purities and crystalline forms, including the anhydrous, hydrated and solvated forms, as it is produced starting substrates produced. The different, so used 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A materials were commercially available or were made in the manner disclosed in the prior art, with the proviso that the present conditions could be guaranteed. In the experiments described in the examples, the content the corresponding 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A products were analyzed by HPLC, and the residual solvent content was determined by GC. Particle sizes and Distributions were obtained by the Malvern method. TGA and DSC measurements were performed on Perkin-Elmer instruments; SEM scans were performed on a Jeol JFM-5800, and the diffraction experiments were on a Bruker Nonius FR591 / Kappa CCD single crystal X-ray diffractometer and a Philips X'PertPRO powder X-ray diffractometer carried out, to collect non-environmental data with an Anton Paar TTK-100 humidity camera was equipped. The crystal structures of the thus produced various Pseudopolymorphs are given in Table 1 below, and the conditions used in their manufacture are given in the tables 2 and 3 indicated.

formulations which is the new isostructural pseudopolymorph of the general formula I, where x = 1, y = 0, of Examples 11 and 14 to 21, are described in Examples 23 and 24, and the Comparative data containing the possible logical bioavailability and the outstanding resolution and stability properties of the new pseudopolymorph relative to the commercial one 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A-dihydrate product are given in Examples 25 to 26.

manufacturing the pseudopolymorph

example 1

Preparation of the pseudopolymorph of formula II (S = acetone, x = 1, y = 0.5) by precipitation Acetone / water

(Method A)

The 9-deoxo-9a-aza-9a-homoerythromycin A (9a-DeMet) intermediate obtained by Method A of US 4,328,334 was treated with formic acid (1.8 to 2.5 mol / mol 9a-DeMet) and formalin (1-1.5 mol formaldehyde / mol 9a-DeMet) in acetone (4-8 l / kg of the 9a-DeMet material ) implemented. The mixture was heated to its boiling point (about 56 ° C) and stirred at this temperature for 4 h.

Subsequently was activated the reaction mixture, and activated carbon was added. After stirring was the mixture filtered off and the carbon remaining on the filter was treated with acetone (0.5-2.0 l / kg of the 9a-DeMet substrate). The combined acetone solution (both the filtrate as well as the wash solution) subsequently the water (10-20 l / kg of 9a-DeMet). The product crystals became so partial precipitated.

The resulting mixture was gradually added with 10% sodium hydroxide made alkaline to a pH of 9.8 and then 2 h stirred at room temperature. The precipitate was a crystalline isostructural pseudopolymorph of the formula I (II: S = acetone, x = 1 and y = 0.5). The rainfall was filtered, with an aqueous acetone solution (10% v / v) and at room temperature under atmospheric pressure dried to a constant weight. So at least 0.7 mol of the isostructural pseudopolymorph produced. By the single crystal X-ray diffraction analysis became the isostructural pseudopolymorph shown in Table 1 below is identified as compound II. The special ones conditions used in the preparation of this pseudopolymorph are summarized in Table 2.

Example 2

Preparation of the pseudopolymorph of the formula Ie (S = isopropanol, x = 1.5, y = 0.5) by precipitation from Isopropanol / water

(Method A)

The native solution of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, as in Example 1 described from 9a-DeMet (1 mol), formic acid (1.8-2.5 mol / mol 9a-DeMet) and Formalin (1-1.5 mol of formaldehyde / mol 9a-DeMet) became isopropanol (4-8 l / kg of the 9a-DeMet material). The mixture was the same Treated as described in Example 1, i. it was up heated to its boiling point and stirred at this temperature for 4 h. Subsequently was the reaction mixture cooled, and activated carbon was added. After stirring, the mixture was filtered, and those remaining on the filter Coal was treated with isopropanol (0.5-2.0 l / kg of the 9a DeMet substrate) washed. The combined isopropanol solution (both the filtrate and the wash solution) was then the Water (10-20 l / kg of 9a-DeMet). Thus, product crystals were precipitated.

The resulting mixture was gradually treated with 10% sodium hydroxide made alkaline to a pH of 9.8 and then another 2 h stirred at room temperature. The precipitate was a crystalline isostructural pseudopolymorph of the formula Ie in the form of an isopropanol solvate (S = isopropanol, x = 1.5 and y = 0.5). The precipitate was filtered, with a aqueous isopropanol (10% v / v) and at a temperature of 70-80 ° C under a reduced pressure of 3-5 kPa dried to a constant weight. There were thus at least 0.7 mol of the isostructural Pseudopolymophs Ie produced. By the single-crystal X-ray diffraction analysis was the isostructural pseudopolymorph, as indicated in Table 1, characterized. The special ones used in the manufacture Conditions are disclosed in Table 2.

Example 3:

Preparation of the pseudopolymorph of the formula Id (S = n-propanol, x = 1, y = 0.5) by precipitation n-propanol / water

(Method B)

raw 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (5 g) with a water content of 5.7 mol% was added with stirring dissolved in 20 ml of n-propanol and heated to a temperature of 40-50 ° C. The solution was treated with charcoal, filtered and over a 2 hour period to a temperature of 35 ° C cooled. The mixture was mixed with 0.25 g of the isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of the formula Ie (S = n-propanol, x = 1 and y = 0.5) inoculated and during 24 h at 0 ° C cooled. The precipitate thus formed was the crystalline isostructural Pseudopolymorph in the form of n-propanol solvate. The rainfall was filtered, washed with cold n-propanol and under a reduced pressure of 6-8 kPa and at a temperature of 40 ° C up to dried at a constant weight. Thus, 2.6 g of the isostructural Pseudopolymorphs Id, characterized as indicated in Table 1, produced. The conditions used in the production are in Table 2.

Example 4:

Preparation of the pseudopolymorph of the formula Ig (S = isobutanol, x = 1.25, y = 0.5) by precipitation Isobutanol / water

(Method C)

amorphous 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (5 g) with a water content of 3.8 mol% was dissolved in 15 ml of isobutane and allowed to reach a temperature from 40 ° C heated. At this temperature, the solution was gradually submerged under water stir added until a slight haze formed. Subsequently was the solution gradually during Cooled to room temperature for 5 h and at this temperature without stirring left another 18 h. The resulting precipitate was a crystalline isostructural pseudopolymorph of the formula Ig in the form of an isobutanol solvate (S = isobutanol, x = 1.25 and y = 0.5). The precipitate was filtered off, with a cold aqueous solution of isobutanol (10% v / v) and at atmospheric pressure and dried at room temperature to a constant weight. Thus, 2.2 g of the pseudopolymorph Ig was prepared. By single-crystal X-ray diffraction analysis the crystal structure characterized in Table 1 was identified. The conditions of the preparative Technique are disclosed in Table 2.

Example 5:

Preparation of the pseudopolymorph of the formula Ic (S = ethanol, x = 1, y = 0.5) by precipitation Ethanol / water

(Method D)

9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate (5 g, purity: USP 25) was dissolved in 35 ml of 96% ethanol. The stirred solution was heated to a temperature of 30-40 ° C and then after and after a period of 2 h at 40 ° C inoculated with 50 mg of the isostructural pseudopolymorph of Formula Ia, where x = 1 and y = 0, added to 70 ml of water. Subsequently The mixture was gradually added over a period of 24 h at 5 ° C cooled to form a precipitate. The rainfall was filtered, washed with cold 96% ethanol and under atmospheric pressure and at a temperature of 0 ° C up to 10 ° C dried to a constant weight. There were 2.0 g of the Pseudopolymorphs Ic obtained. After the single-crystal X-ray diffraction analysis was the isostructural pseudopolymorph characterized in Table 1 Ic identified. The parameters of the preparative technique are shown in Table 2 discloses.

Examples 6-9:

Production of pseudopolymorphs of the formulas Ij (S = glycerol, x = 1, y = 0.5), Ik (S = glycerol, x = 1.5, y = 0.5), Ib (S = methanol, x = 1.25, y = 1); and Im (p = DMSO, x = 1, y = 0.5)

Corresponding in Examples 3-5 executed Procedures were the crystalline isostructural pseudopolymorphs of the formula I in the form of the glycerol sulfates Ij (S = glycerol, x = 1 and y = 0.5) and Ik (S = glycerol, x = 1.5 and y = 0.5), the methanolic novate Ib (S = methanol, x = 1.25 and y = 1) and the dimethyl sulfoxide (DMSO) solvate Im (S = DMSO, x = 1 and y = 0.5) produced. By the single-crystal X-ray diffraction analysis were the corresponding pseudopolymorphs Ij, Ik, Ib and Im, as in Table 1. The preparative conditions are in Table 2.

Example 10:

Production of pseudopolymorphs of the formulas Ih (S = 1,2-ethanediol, x = 1, y = 0.5) by precipitation from 1,2-ethanediol

(Method E)

60 ml of a native solution of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A in ethyl acetate, prepared as described in WO 01/00640 diluted with an additional 40 ml of ethyl acetate. The resulting mixture was gradually added with 10% NaOH solution alkalized to a pH of 9.8, and the layers were separated. The ethyl acetate layer was washed with a saturated Sodium chloride solution washed and treated with charcoal. Then the mixture was filtered, and those remaining on the filter Coal was washed with ethyl acetate (5 ml). The combined ethyl acetate solution (both the filtrate as well as the washing solution) 30 ml of 1,2-ethanediol were added. Subsequently, the ethyl acetate at atmospheric pressure distilled off. The residue after the distillation was during slowly cooled from 90 ° C to 0 ° C over a period of 30 hours.

Of the resulting precipitate was a crystalline isostrukturelles Pseudopolymorph of the formula Ih in the form of a 1,2-ethanediol solvate (S = 1,2-ethanediol, x = 1 and y = 0.5). The precipitate was filtered, with a cold watery solution of 1,2-ethanediol (10% v / v) and at atmospheric pressure and at a temperature of 0 ° C up to 10 ° C dried to a constant weight. Thus, 3.4 g of the pseudopolymorph I made it. By the single-crystal X-ray diffraction analysis was the isostructural pseudopolymorph Ih, as indicated in Table 1, characterized. The preparative Conditions are summarized in Table 2.

Example 11:

Transformation of pseudopolymorph II (S = acetone, x = 1, y = 0.5) into the pseudopolymorph Ia (x = 1, y = 0)

A native dichloromethane solution of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A prepared using the methods described in U.S. Patent No. 4,474,768 was described using the method described in the Examples 10 and 5 procedures described above the methods E and D into a crystalline isostructural pseudopolymorph of formula II (S = acetone, x = 1 and y = 0.5) converted. The precipitate thus formed was filtered off and washed with an aqueous acetone solution (10%). Vol./Vol.). After drying under reduced pressure of 2-5 kPa and at a temperature of 70 ° C to 80 ° C were 0.6 mol Pseudopolymorph Ia (x = 1, y = 0) (purity: USP 25). The crystal structure of pseudopolymorph Ia was characterized as in Table 1 specified. The conditions used are summarized in Table 2.

Examples 12-13:

Production of pseudopolymorphs of the formulas If (S = n-butanol, x = 1.5, y = 0.5) and Ii (S = 1,3-propanediol, x = 1, y = 0.5)

A native chloroform solution of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A prepared according to the procedure described in U.S. Patent No. 4,517,359 was added to the pseudopolymorph If (S = n-butanol, x = 1 , 5 and y = 0.5) converted. A native butyl acetate solution of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, prepared according to the method disclosed in WO 99/58541 example, was converted into the pseudopolymorph Ii (S = 1,3-propanediol, x = 1 and y = 0.5).

The Pseudopolymorphs were prepared according to the methods described in Examples 3, 5, 10 and 11 described procedures by the method E and B and E and D. By the single-crystal X-ray diffraction analysis were the pseudopolymorphs If and Ii, as indicated in Table 1, characterized. The conditions used are summarized in Table 2.

Example 14:

Transformation of pseudopolymorph II (S = acetone, x = 1, y = 0.5) into the pseudopolymorph Ia (x = 1, y = 0)

The Pseudopolymorph II (S = acetone, x = 1, y = 0.5), obtained according to Example 1, was under a reduced pressure of 0.1 kPa and at a Temperature of 50 ° C dried to a constant weight. The resulting pseudopolymorph was characterized as Formula Ia (x = 1 and y = 0, Table 1). The yield was quantitative; Purity: according to USP 25.

Example 15:

Transformation of pseudopolymorph Ic (S = ethanol, x = 1, y = 0.5) into the pseudopolymorph Ia (x = 1, y = 0)

The Pseudopolymorphic Ic (S = ethanol, x = 1, y = 0.5), prepared as described in Example 5 was under a reduced pressure of 2 kPa and at a temperature of 80 ° C to constant weight dried. The resulting pseudopolymorph Ia was in the form and yield identical to that prepared in Example 14.

Example 16:

Transformation of pseudopolymorph Ib (S = methanol, x = 1.25, y = 1) into the pseudopolymorph Ia (x = 1, y = 0)

The obtained according to Example 8 crystalline pseudopolymorph Ib (S = methanol, x = 1.25 and y = 1) was under a reduced pressure of 2 kPa and at a temperature of 80 ° C dried to a constant weight. The resulting, in Table 1 characterized Pseudopolymorph Ia was in shape and yield identical to that obtained in Example 14.

Example 17:

Transformation of pseudopolymorph Id (S = n-propanol, x = 1, y = 0.5) into the pseudopolymorph Ia (x = 1, y = 0)

The crystalline pseudopolymorph Id obtained according to Example 3 (S = n-propanol, x = 1 and y = 0.5) was under a reduced pressure of 13 Pa and at a temperature of 80 ° C dried. Yield and purity of the pseudopolymorph thus prepared Ia (x = 1 and y = 0) were identical to those of Example 14.

Example 18:

Transformation of pseudopolymorph Ie (S = iso-propanol, x = 1.5, y = 0.5) into the pseudopolymorph Ia (x = 1, y = 0)

The obtained according to Example 2 crystalline pseudopolymorph Ie (S = isopropanol, x = 1.5 and y = 0.5), was under a reduced pressure of 1 Pa and subjected to a sublimation at a temperature of -95 ° C, until a product of constant weight was produced. yield and purity of the pseudopolymorph Ia (x = 1 and y = 0) were too identical to those of Example 14.

Example 19:

Conversion of crude 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A into the pseudopolymorph Ia (x = 1, y = 0)

The crude commercial 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (100 g) was suspended in 500 ml of water and gradually added at room temperature over a period of 105 min using 10% hydrochloric acid to a pH of 5 , 2 acidified. The resulting solution was then added dropwise over about 35 minutes at room temperature to 1360 ml of about 3% acetone (formed by adding 1320 ml of water to 40 ml of acetone). To this solution, a 10% sodium hydroxide solution was added dropwise over 55 minutes at room temperature until a pH of 9.8 was obtained. Subsequently, the mixture was heated to 40 ° C, stirred at this temperature for 120 minutes and then cooled to 30 ° C. The precipitate was a crystalline isostructural pseudopolymorph II (S = acetone, x = 1, y = 0.5). The precipitate was filtered off and washed twice with 30 ml of a 10% acetone solution. Thus, 234.1 g of wet pseudopolymorph II (S = acetone, x = 1, y = 0.5) was obtained which after drying to a constant weight at 55 ° C under a vacuum of 2.0 kPa 93.5 g of the isostructural pseudopolymorph Ia (x = 1 and y = 0) with a USP purity of 25 (lot 1).

The Repeating this procedure twice (batches 2 and 3) gave the pseudopolymorph Ia (x = 1 and y = 0) in yields of 92.5 g (batch 2) and 93.8 g (batch 3). USP purity 25.

Example 20:

Conversion of crude 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A into the pseudopolymorph Ia (x = 1, y = 0)

The raw commercial 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (40g) was prepared in 200 ml of water and stepwise at room temperature for about 60 acidified to a pH of 5.5. The resulting solution was at room temperature during To 600 ml of a 10% acetone solution (formed by addition from 60 ml of acetone to 540 ml of water) was added dropwise. This solution was at room temperature during a 10% potassium carbonate solution was added dropwise over a period of 80 minutes, until a pH of 9.8 was reached, with simultaneous inoculation with 0.8 g of the pseudopolymorph II (S = acetone, x = 1 and y = 0.5). The mixture was subsequently stirred at room temperature for a further 15 min. The resulting crystals were filtered, washed twice with 20 ml of a 10% acetone solution and at 2.0 kPa and at a temperature of 75 ° C under vacuum up to one dried constant weight. Thus, 37.5 g of the isostructural Pseudopolymorphs Ia (x = 1 and y = 0).

Example 21:

Transformation of pseudopolymorph II (S = acetone, x = 1 and y = 0.5) into the pseudopolymorph Ia (x = 1, y = 0)

40 g of the isostructural pseudopolymorph II (S = acetone, x = 1 and y = 0.5) were suspended in 200 ml of water and at room temperature for about 60 min with 10% acetic acid acidified to a pH of 5.5 until the pseudopolymorph II solved would have. The resulting solution was at room temperature during To 600 ml of a 10% acetone solution (formed by addition from 60 ml of acetone to 540 ml of water) was added dropwise. This solution was at room temperature during A 10% sodium hydroxide solution was added dropwise for 80 min until a pH of reached 9.8 with simultaneous inoculation with 0.4 g of isostructural pseudopolymorph II (S = acetone, x = 1, y = 0.5). Subsequently was the mixture for stirred for a further 15 min at room temperature. The resulting crystals were filtered, washed twice with 20 ml of a 10% acetone solution and under a vacuum of 2.0 kPa at 55 ° C to a constant weight dried. Thus, 35.5 g of the isostructural pseudopolymorph Ia (x = 1 and y = 0).

Example 22:

Reprecipitation of Pseudopolymorph Im (S = DMSO, x = 1 and y = 0.5)

TABELLE 3: BILDUNG VON ISOSTRUKTURELLEM 9-DEOXO-9a-AZA-9a-METHYL-9a-HOMOERYTHROMYCIN A-PSEUDOPOLYMORPH Ia (x = 1, y = 0)

• 1. Pseudopolymorph II (S = Aceton, x = 1, y = 0,5), hergestellt aus rohem 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A und nassem in situ getrocknetem Solvat
• 2. Pseudopolymorph II (S = Aceton, x = 1, y = 0,5), kristallisiert unter Anwendung der Impftechnik

2.0 g of the isostructural pseudopolymorph Im (S = DMSO, x = 1 and y = 0.5) obtained as described in Example 9 were dissolved in 10 ml of DMSO at a temperature of 50 ° C. The solution was added dropwise to water at a temperature until it became slightly cloudy. The mixture was then cooled to room temperature over a period of 2 hours and held at this temperature for a further 72 hours. The precipitated crystalline isostructural pseudopolymorph Im (S = DMSO, x = 1 and y = 0.5) was filtered off, washed with cold water and dried at atmospheric pressure and a temperature of 25 ° C to a constant weight. Thus, 1.1 g of the recrystallized pseudopolymorph Im (S = DMSO, x = 1, y = 0.5) was obtained.

TABLE 3: FORMATION OF ISOSTRUCTURELLE 9-DEOXO-9a-AZA-9a-METHYL-9a-HOMOERYTHROMYCIN A-PSEUDOPOLYMORPH Ia (x = 1, y = 0)

• 1. Pseudopolymorph II (S = acetone, x = 1, y = 0.5) prepared from crude 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A and wet in situ dried solvate
• 2. Pseudopolymorph II (S = acetone, x = 1, y = 0.5) crystallized using the seed technique

formulations the pseudopolymorph

Example 23:

Tablet formulations

9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorph formulations were prepared by granulating the isostructural pseudopolymorph (97%) of Examples 11 and 14 to 21 (x = 1 and y = 0) with starch, microcrystalline Cellulose and croscaramellose sodium prepared by granulation standard techniques. The dried granules were homogenized with magnesium stearate and tabletted using a standard tabletting machine. The tablet cores were coated with a hydroxypropyl methylcellulose (HPMC) coating. The amounts of ingredients for 150, 200, 250, 300, 500 and 600 mg tablets are given in Table 4. Table 4: TABLET FORMULATIONS OF 9-DEOXO-9a-AZA-9a-METHYL-9a-HOMOERYTHROMYCIN A-MONOHYDRATPSEUDOPOLYMORPH (x = 1, y = 0)

Example 24:

Topical formulations

Water, cosolvent (Glycerin, polyethylene glycol), preservatives (methyl and Propylparaben), stabilizer and gelling polymer are passed through homogenized the standard technique to form an aqueous phase.

The isostructural pseudopolymorph Ia (x = 1 and y = 0) was added to such an aqueous phase, and it was dispersed / dissolved. The oily components (such as liquid paraffin and cetyl alcohol) with the addition of emulsifier were melted, and after cooling, they were mixed with the previously prepared aqueous phase. The final homogenization was carried out under reduced pressure. The finished phase, ie a homogeneous gel, an odorant can be added and optionally their pH can be adjusted. A typical pseudopolymorph-containing formulation thus prepared is shown in Table 5. TABLE 5 TOPICAL FORMULATION THE ISOSTRUCTURAL 9-DEOXO-9a-AZA-9a-METHYL-9a-HOMOERYTHROMYCIN A-PSEUDOPOLYMORPH Ia CONTAINS

In These mixtures may have a wide range of concentrations isostructural pseudopolymorphs of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A be used; also a preservative can, depending on the dosage form (i.e., multiple or single dose), be incorporated into the preparation.

The towering Properties of the isostructural invention Pseudopolymorphs

Example 25:

Dissolution profiles of the new invention Pseudopolymorphs vs. handeslüblichem 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate

To compare the behavior in vitro of the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorph Ia according to the invention with the commercially available 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate product, the Dissolution profiles at pH 3 and pH 6 at 37 ° C determined. For comparison, 3 batches of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorph Ia from Example 19 were used above. The comparative dissolution profiles were determined by USP Method 2, PharmaTest Dissolution Tester, PTW SII; the content of dissolved 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A was measured by HPLC. The data thus obtained are shown in Table 6 below and in the 17 and 18 applied. TABLE 6 PERCENT OF 9-DEOXO-9a-AZA-9a-METHYL-9a-HOMOERYTHROMYCIN A-PSEUDOPOLYMORPH Ia AND SOLVED TRADING 9-DEOXO-9a-AZA-9a-METHYL-9a-HOMOERYTHROMYCIN A-DIHYDRATE PRODUCT

In addition to the above data, for the novel pseudopolymorph of the invention and the commercial dihydrate, natural dissolution rates (IDR's) at pH 3 and pH 6 and 37 ° C were determined by the Intrinsic Dissolution Tester, Type Van Kel. For the novel pseudopolymorph, the IDR was about 2.5 to 2.8 mg min ^-1 cm ^-2 , about 40 to 50% above the IDR of the prior art 9-deoxo-9a-aza-9a-methyl- 9a homoerythromycin A dihydrate (about 1.8 mg min ^-1 cm ^-2 ).

Example 26:

Comparison of the dissolution profiles of 3 batches of the novel pseudopolymorph according to the invention and of the commercial one 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate

Around to further evaluate the data from Table 6 were similarity factors (f2) according to the Note for Guidance on the Investigation of Bioavailability and Bioequivalence (EMEA, December 1998, London) for the dissolution profiles of the two species (inventive 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A-pseudopolymorph Ia and commercial 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate).

A similarity factor (f2) between 50 and 100 suggests that the two dissolution profiles compared are similar and suggests that they have similar bioavailability. On the other hand, f2 values below 50 show significant differences in the two dissolution profiles and therefore in their relative bioavailability. A comparison of the calculated f2 values for the corresponding pairs of the 3 batches of the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorph Ia prepared according to Example 19 (x = 1, y = 0) are shown in Table 7 indicated. Also reported is a comparison of the f2 values for each lot of Example 19 as compared to the commercial 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate product. TABLE 7: Calculated Similarity Factors for the 9-DEOXO-9a-AZA-9a-METHYL-9a-HOMOERYTHROMYCIN A-PSEUDOPOLYMORPH Ia FROM EXAMPLE 19 AND FOR THE MANUFACTURED 9-DEOXO-9a-AZA-9a-METHYL-9a-HOMOERYTHROMYCIN A- dIHYDRATE PRODUCT

To Table 7 shows lots 1, 2 and 3 of the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorph Ia (x = 1, y = 0) of Example 19 Similar Dissolution Profiles (and therefore similar bioavailability) on, whereas the dissolution profiles of the dihydrate relative to each batch of the novel pseudopolymorph of the invention unlike are (and therefore the bioavailability as expected worth mentioning differs). Given these characteristics would be expected be that the pseudopolymorphs of the invention outstanding reproducible release characteristics, in particular with regard to immediate or controlled releasing formulations would have.

Example 27:

Solid state stability of the new invention

Pseudopolymorphs Ia

The solid state stability of the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorph Ia (x = 1, y = 0) was determined by measuring the solid state X-ray powder diffraction pattern for this material at 4 different relative humidities in% (%). RH) in the range of 5 to 75% RH and at five different temperatures, increasing from 30 to 75 ° C, using a Philips X'PertPRO powder X-ray diffractometer equipped with an Anton Paar TTK-100 humidity camera not suitable for use Environment Data Collection was used. The results are in 19 shown. As explained, no phase transitions occur, ie there is no interconversion of the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorph Ia (x = 1, y = 0) to any other form, either the temperature or relative humidity increases.

Example 28:

Pharmacokinetic in vivo Profiles of the novel pseudopolymorph Ia vs. commercial 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate

To compare the behavior in vivo of the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorph Ia according to the invention with the commercially available 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate product Plasma and whole blood concentration-time curves were determined in rats after per os administration at a concentration of 50 mg / kg body weight. Thirty-two animals were studied using a crossover experiment setup. Non-compartmental analysis was used to determine the concentrations of the respective materials in whole blood and plasma as a function of time. The data thus obtained are in the 20 and 21 executed.

The pharmacokinetic parameters for the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorph Ia according to the invention and the commercial 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate product in whole blood and plasma in rats after a per os dose of 50 mg / kg body weight are shown in Table 8 below. TABLE 8 PHARMACOKINETIC IN VIVO PARAMETERS FOR THE 9-DEOXO-9a-AZA-9a-METHYL-9a-HOMOERYTHROMYCIN A-PSEUDOPOLYMORPH Ia AND THE MANUFACTURED 9-DEOXO-9a-AZA-9a-METHYL-9a-HOMOERYTHROMYCIN A-DIHYDRATE

As indicated in Table 8, in both whole blood and plasma, higher concentrations of the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorph Ia of this invention are compared to the commercial 9-deoxo-9α aza-9a-methyl-9a-homoerythromycin A dihydrate product detected after per os administration. The largest concentration difference between the two 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A products is observed after 2 hours (T _max ).

Higher AUC values were found especially for the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorph Ia during the first 12 hours after administration. The calculated AUC value for the first 0-12 hours, AUC _(0-12) , is relative in both whole blood and plasma for the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorph Ia to the commercial 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate product, surprisingly about 20% higher.

The Results suggest a faster absorption, higher bioavailability and faster distribution of the 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorphs Ia into the cells and / or Tissue relative to the commercial one 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate product.

Example 29:

Dissolution profiles of the novel pseudopolymorph according to the invention Ik (S = glycerol, x = 1.5, y = 0.5) vs. commercial 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate

To the in vitro behavior of the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorph Ik according to the invention with the commercially available 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate product were compared, the dissolution profiles were determined at pH 6 at 37 ° C. For comparison, the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorph Ik of Example 6 was used. The comparative dissolution profiles were determined by USP Method 2, PharmaTest Dissolution Tester, PTW SII; the content of dissolved 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A was measured by HPLC. The data thus obtained are listed in Table 9 below and in 22 applied. TABLE 9 PERCENT SOLVED 9-DEOXO-9a-AZA-9a-METHYL-9a-HOMOERYTHROMYCIN A-PSEUDOPOLYMORPHIC AND SOLVED COMMERCIAL 9-DEOXO-9a-AZA-9a-METHYL-9a-HOMOERYTHROMYCIN A-DIHYDRATE PRODUCT

• 1. Ein Verfahren zur Herstellung eines im Wesentlichen reinen isostrukturellen Pseudopolymorphs von 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A mit der Formel I:
  
  wobei S ein organisches Lösungsmittel ist, das zumindest teilweise mit Wasser mischbar ist, x 1, 1,25, 1,5 oder 2 ist, y 0, 0,5 oder 1 ist, wobei das Pseudopolymorph durch die monokline Raumgruppe P2₁, und die durchschnittlichen Einheitszellenparameter gekennzeichnet ist, umfassend Kristallachsenlängen von a = 15,5–17,0 Å, b = 15,5–17,0 Å und c = 17,5–19,5 Å, und Winkel zwischen den Kristallachsen von α = γ = 90° und β = 106°–112°; wobei das Verfahren umfasst: (a) Auflösen eines 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A-Materials in (1) einem organischen Lösungsmittel, das zumindest teilweise wassermischbar ist, (2) einem Gemisch von solchen organischen Lösungsmitteln, (3) einem Gemisch des organischen Lösungsmittels mit Wasser oder (4) einem Gemisch von Wasser und mindestens einer mineralischen oder organischen Säure; (b) Kristallisieren des isostrukturellen Pseudopolymorphs aus der Lösung; (c) Isolieren des isostrukturellen Pseudopolymorphs; und (d) Umwandeln des isostrukturellen Pseudopolymorphs der Formel I in ein stabiles isostrukturelles Pseudopolymorph der Formel Ia, wobei x = 1 und y = 0 bedeuten.
• 2. Das Verfahren nach Aspekt 1, wobei das in Schritt (a) gelöste 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A-Material folgendes ist (i) ein kristallines 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, entweder in roher oder gereinigter Form, (ii) ein amorphes 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, entweder in roher oder gereinigter Form, (iii) Solvate oder Hydrate von 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, entweder in roher oder in gereinigter Form oder (iv) eine native Lösung von 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, das während des letzten Schrittes seiner Synthesen aus einer seiner letzten Zwischenstufen gebildet wird.
• 3. Das Verfahren nach Aspekt 2, wobei das zur Herstellung neuer Pseudopolymorphe verwendete 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A-Material, das in Schritt (a) gelöst wird, ein rohes 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A in einer von seinen bekannten Formen und mit weniger als einer pharmazeutisch verträglichen Reinheit ist.
• 4. Das Verfahren nach Aspekt 2, wobei die native, zur Herstellung neuer Pseudopolymorphe verwendete Lösung von 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, das in Schritt (a) gelöst wird, eine Lösung von 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A ist, das in der nativen Lösung während des letzten Schrittes seiner Synthese aus einer seiner letzten Zwischenstufen gebildet wird.
• 5. Das Verfahren nach Aspekt 2, wobei die zur Herstellung neuer Pseudopolymorphe verwendete native Lösung von 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, gelöst in Schritt (a), eine Lösung von 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A ist, das in der nativen Lösung während des letzten Schrittes seiner Synthese aus 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A als seine letzte Zwischenstufe gebildet wird.
• 6. Das Verfahren nach Aspekt 2, wobei das in Schritt (a) gelöste 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A in Form einer Dispersion von 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A und der 9-Deoxo-9a-aza-9a-homoerythromycin A-Zwischenstufe in der nativen Lösung vorliegt, die in dem letzten Stadium der Synthese von rohem 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A verwendet wird.
• 7. Das Verfahren nach Aspekt 4, wobei das Lösungsmittel in der nativen Lösung ausgewählt ist aus der Gruppe, bestehend aus einem oder mehreren Halogenalkanen mit ein oder zwei Kohlenstoffatomen, Estern von Essigsäure mit einer C₂-C₄-Niederalkylgruppe, einwertigen C₂-C₄-Alkanolen, C₁-C₄-Ketonen, aromatischen oder substituierten aromatischen Verbindungen oder einem Gemisch davon.
• 8. Das Verfahren nach Aspekt 2, wobei das in Schritt (a) gelöste 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A folgendes ist (a) amorphes 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A; ein kristallines, wasserfreies Monohydrat, Dihydrat oder Solvatform von 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A oder ein isostrukturelles Pseudopolymorph von 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A der Formel I.
• 9. Das Verfahren nach Aspekt 2, wobei das in Schritt (a) gelöste 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A von pharmazeutisch verträglicher Reinheit ist.
• 10. Das Verfahren nach Aspekt 1, wobei Schritt (a) bei einer Temperatur von etwa 20°C bis etwa 100°C durchgeführt wird.
• 11. Das Verfahren nach Aspekt 1, wobei das organische Lösungsmittel, in dem das in Schritt (a) gelöste 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A ein oder mehrere niederaliphatische geradkettige oder verzweigte Alkanole, Cycloalkanole, Arylalkanole, Diole, Triole, Ether, Ketone, Ester, Amide, Harnstoffe, Nitrile, Sulfoxide oder Sulfone; eine oder mehrere heterocyclische Amine oder Lactame; oder Gemische davon ist.
• 12. Verfahren nach Aspekt 1, wobei das 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A-Pseudopolymorph in Schritt (b) durch kontrolliertes Abkühlen der Lösung, enthaltend das 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, bei Temperaturen von etwa 80°C bis etwa –10°C kristallisiert wird.
• 13. Das Verfahren nach Aspekt 1, wobei das 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A-Pseudopolymorph in Schritt (b) isotherm bei einer Temperatur von etwa 25 bis etwa 60°C durch Stehen lassen oder Mischen der Lösung, die in Schritt (a) in einem organischen Lösungsmittel, das unter den angegebenen isothermen Bedingungen zumindest teilweise wassermischbar ist, kristallisiert wird.
• 14. Verfahren nach Aspekt 1, wobei das 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A-Pseudopolymorph in Schritt (b) bei einer Temperatur von etwa 25 bis etwa 60°C durch Sättigung der Lösung kristallisiert wird, die in Schritt (a) in einem organischen Lösungsmittel, das zumindest teilweise wasserlöslich ist, mit Wasser bis zur leichten Trübung der Lösung kristallisiert wird.
• 15. Das Verfahren nach Aspekt 1, wobei das 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A-Pseudopolymorph in Schritt (b) durch Neutralisieren der wässrigen sauren Lösung von 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, die in Schritt (a) gebildet wird, bei Temperaturen von etwa 80 bis etwa –10°C kristallisiert wird.
• 16. Das Verfahren nach Aspekt 1, wobei das isostrukturelle Pseudopolymorph von 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A der Formel I der Lösung in Schritt (b) in einer Menge von etwa 0,01 bis etwa 5,0 Gew.-%, bezogen auf die Menge des 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A-Ausgangsmaterials zugesetzt wird, um Kristallisationskeime des isostrukturellen Pseudopolymorphs einzubringen.
• 17. Das Verfahren nach Aspekt 1, wobei das 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A-Pseudopolymorph der Formel I in Schritt (c) isoliert wird durch: (i) Abtrennen des Pseudopolymorphs von der in Schritt (a) gebildeten Lösung; (ii) Waschen des resultierenden Produkts mit Lösungsmitteln (1), (2) oder (3), die in Schritt (a) verwendet werden, bei Temperaturen von etwa –10 bis etwa 40°C; und (iii) Trocknen des gewaschenen Produkts unter Atmosphärendruck bei Temperaturen von etwa 20 bis etwa 120°C oder unter reduzierten Drücken von etwa 2 kPa bis etwa 80 kPa.
• 18. Das Verfahren nach Aspekt 1, wobei das Pseudopolymorph der Formel I in Schritt (d) in das stabile isostrukturelle Pseudopolymorph der Formel Ia, wobei x = 1 und y = 0 bedeuten, durch Lyophilisieren oder weiteres Trocknen des Pseudopolymorphs bei Atmosphärendruck oder bei reduzierten Drücken von etwa 0,01 bis etwa 80 kPa und Temperaturen von etwa –100°C bis etwa 120°C übergeführt wird.
• 19. Das Verfahren nach Aspekt 1, wobei das Pseudopolymorph der Formel I (Ia: x = 1, y = 0), in Schritt (d) gebildet wird, das durch die monokline Raumgruppe P2₁ mit den Einheitszellenparametern bei einer Temperatur von 22°C von a = 16,368(5) Å, b = 16,301(3) Å, c = 18,408(5) Å, α = γ = 90°, und β = 110,04(2)° gekennzeichnet ist.
• 20. Das im Wesentlichen reine isostrukturelle Pseudopolymorph der Formel I, das durch das Verfahren nach Aspekt 1 hergestellt wird.
• 21. Das im Wesentlichen reine isostrukturelle Pseudopolymorph der Formel Ia, das durch das Verfahren von Aspekt 1 hergestellt wird, das durch monokline Raumgruppe P2₁ mit den durchschnittlichen Einheitszellenparametern bei einer Temperatur von 22°C von a = 16,368(5) Å, b = 16,301(3) Å, c = 18,408(5) Å, α = γ = 90°, und β = 110,04(2)° gekennzeichnet ist.
• 22. Ein im Wesentlichen reines isostrukturelles Pseudopolymorph von 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A mit der Formel I:
  
  wobei S ein organisches Lösungsmittel ist, das zumindest teilweise mit Wasser mischbar ist, x 1, 1,25, 1,5 oder 2 ist, y 0, 0,5 oder 1 ist, wobei das Pseudopolymorph durch die monokline Raumgruppe P2₁ und die durchschnittlichen Einheitszellenparameter von Kristallachsenlängen von a = 15,5–17,0 Å, b = 15,5–17,0 Å und c = 17,5–19,5 Å, und Winkeln zwischen den Kristallachsen von α = γ = 90° und β = 106°–112° gekennzeichnet ist.
• 23. Das im Wesentlichen reine isostrukturelle Pseudopolymorph nach Aspekt 22, ausgewählt aus der Gruppe von Pseudopolymorphen (Ia)–(Im), die nachstehend ausgeführt sind, wobei x, y und S in Formel I und die durchschnittlichen Einheitszellenparametern, d.h. die Kristallachsenlängen a, b und c und die Winkel α, β und γ zwischen den Kristallachsen der Kristallstrukturen, folgende sind: (Ia) x = 1, y = 0 und bei 22°C: a = 16,368(5) Å, b = 16,301(3) Å, c = 18,408(5) Å, α = γ = 90° und β = 110,04(2)°. (Ib) x = 1,25, y = 1 (S = MeOH) und bei 22°C: a = 16,546(3) Å, b = 16,185(6) Å, c = 18,511(7) Å, α = γ = 90° und β = 110,53(3)°. (Ic) x = 1, y = 0,5 (S = EtOH) und bei –173°C: a = 16,1400(10) Å, b = 16,1530(10) Å, c = 18,2640(10) Å, α = γ = 90° und β = 109,590(10)°. (Id) x = 1, y = 0,5 (S = n-PrOH) und bei 22°C: a = 16,32(2) Å, b = 16,344(16) Å, c = 18,610(18) Å, α = γ = 90° und β = 108,88(9)°. (Ie) x = 1,5, y = 0,5 (S = i-PrOH) und bei 22°C: a = 16,29410(10) Å, b = 16,24440(10) Å, c = 18,80600(10) Å, α = γ = 90°, und β = 108,5701(3)°. (If) x = 1,5, y = 0,5 (S = n-BuOH) und bei –173°C: a = 16,1580(10) Å, b = 16,0190(10) Å, c = 18,4570(10) Å, α = γ = 90° und β = 108,866(10)°. (Ig) x = 1,25, y = 0,5 (S = i-BuOH) und bei 22°C: a = 16,166(8) Å, b = 16,123(4) Å, c = 18,591(14) Å, α = γ = 90° und β = 107,68(14)°. (Ih) x = 1, y = 0,5 (S = 1,2-Ethandiol) und bei 22°C: a = 16,232(15) Å, b = 16,213(10) Å, c = 18,531(9) Å, α = γ = 90° und β = 109,63(3)°. (Ii) x = 1, y = 0,5 (S = 1,3-Propandiol) und bei 22°C: a = 16,001(6) Å, b = 16,21(2) Å, c = 18,497(11) Å, α = γ = 90° und β = 109,20(6)°. (Ij) x = 1, y = 0,5 (S = Glycerin) und bei 22°C: a = 16,20(4) Å, b = 16,253(13) Å, c = 18,613(10) Å, α = γ = 90° und β = 109,30(5)°. (Ik) x = 1,5, y = 0,5 (S = Glycerin) und bei 22°C: a = 16,303(6) Å, b = 16,304(4) Å, c = 18,725(13) Å, α = γ = 90° und β = 108,968(15)°. (Il) x = 1,5, y = 0,5 (S = Aceton) und bei 22°C: a = 16,370(6) Å, b = 16,235(7) Å, c = 18,538(7) Å, α = γ = 90° und β = 109,09(3)°. (Im) x = 1, y = 0,5 (S = DMSO) und bei 22°C: a = 16,349(3) Å, b = 16,304(3) Å, c = 18,401(3) Å, α = γ = 90° und β = 108,948(12)°.
• 24. Das im Wesentlichen reine isostrukturelle Pseudopolymorph nach Aspekt 22, das die Strukturparameter: x = 1, y = 0 besitzt und durch die monokline Raumgruppe P2₁ und die Einheitszellenparameter, d.h. die Kristallachsenlängen a, b und c und die Winkel α, β und γ zwischen den Kristallachsen bei einer Temperatur von 22°C von a = 16,368(5) Å, b = 16,301(3) Å, c = 18,408(5) Å, α = γ = 90° und β = 110,04(2)° gekennzeichnet ist.
• 25. Eine pharmazeutische Zubereitung, umfassend ein im Wesentlichen reines isostrukturelles Pseudopolymorph von 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A mit der Formel I:
  
  wobei S ein organisches Lösungsmittel ist, das zumindest teilweise mit Wasser mischbar ist x 1, 1,25, 1,5 oder 2 ist, y 0, 0,5 oder 1 ist, wobei das Pseudopolymorph durch die monokline Raumgruppe P2₁ und die durchschnittlichen Einheitszellenparameter von Kristallachsenlängen von a = 15,5–17,0 Å, b = 15,5–17,0 Å und c = 17,5–19,5 Å und Winkeln zwischen den Kristallachsen von α = γ = 90° und β = 106°–112° gekennzeichnet ist, in Kombination mit einem pharmazeutisch verträglichen Träger.
• 26. Die pharmazeutische Zubereitung nach Aspekt 25, wobei das im Wesentlichen reine isostrukturelle Pseudopolymorph der Formel I aus der Gruppe der Pseudopolymorphe (Ia)-(Im), die nachstehend aufgeführt sind, ausgewählt ist, wobei x, y und S in Formel I und die mittleren Einheitszellenparameter, d.h. die Kristallachsenlängen a, b und c und die Winkel α, β und γ zwischen den Kristallachsen der kristallinen Strukturen, folgende sind: (Ia) x = 1, y = 0 und bei 22°C: a = 16,368(5) Å, b = 16,301(3) Å, c = 18,408(5) Å, α = γ = 90° und β = 110,04(2)°. (Ib) x = 1,25, y = 1 (S = MeOH) und bei 22°C: a = 16,546(3) Å, b = 16,185(6) Å, c = 18,511(7) Å, α = γ = 90° und β = 110,53(3)°. (Ic) x = 1, y = 0,5 (S = EtOH) und bei –173°C: a = 16,1400(10) Å, b = 16,1530(10) Å, c = 18,2640(10) Å, α = γ = 90° und β = 109,590(10)°. (Id) x = 1, y = 0,5 (S = n-PrOH) und bei 22°C: a = 16,32(2) Å, b = 16,344(16) Å, c = 18,610(18) Å, α = γ = 90° und β = 108,88(9)°. (Ie) x = 1,5, y = 0,5 (S = i-PrOH) und bei 22°C: a = 16,29410(10) Å, b = 16,24440(10) Å, c = 18,80600(10) Å, α = γ = 90° und β = 108,5701(3)°. (If) x = 1,5, y = 0,5 (S = n-BuOH) und bei –173°C: a = 16,1580(10) Å, b = 16,0190(10) Å, c = 18,4570(10) Å, α = γ = 90° und β = 108,866(10)°. (Ig) x = 1,25, y = 0,5 (S = i-BuOH) und bei 22°C: a = 16,166(8) Å, b = 16,123(4) Å, c = 18,591(14) Å, α = γ = 90° und β = 107,68(14)°. (Ih) x = 1, y = 0,5 (S = 1,2-Ethandiol) und bei 22°C: a = 16,232(15) Å, b = 16,213(10) Å, c = 18,531(9) Å, α = γ = 90°, und β = 109,63(3)°. (Ii) x = 1, y = 0,5 (S = 1,3-Propandiol) und bei 22°C: a = 16,001(6) Å, b = 16,21(2) Å, c = 18,497(11) Å, α = γ = 90° und β = 109,20(6)°. (Ij) x = 1, y = 0,5 (S = Glycerin) und bei 22°C: a = 16,20(4) Å, b = 16,253(13) Å, c = 18,613(10) Å, α = γ = 90° und β = 109,30(5)°. (Ik) x = 1,5, y = 0,5 (S = Glycerin) und bei 22°C: a = 16,303(6) Å, b = 16,304(4) Å, c = 18,725(13) Å, α = γ = 90° und β = 108,968(15)°. (Il) x = 1,5, y = 0,5 (S = Aceton) und bei 22°C: a = 16,370(6) Å, b = 16,235(7) Å, c = 18,538(7) Å, α = γ = 90° und β = 109,09(3)°. (Im) x = 1, y = 0,5 (S = DMSO) und bei 22°C: a = 16,349(3) Å, b = 16,304(3) Å, c = 18,401(3) Å, α = γ = 90° und β = 108,948(12)°.
• 27. Die pharmazeutische Zubereitung nach Aspekt 25, wobei das im Wesentlichen reine isostrukturelle Pseudopolymorph die Strukturparameter: x = 1, y = 0 besitzt und durch die monokline Raumgruppe P2₁ und die Einheitszellenparameter, d.h. die Kristallachsenlängen a, b und c und die Winkel α, β und γ zwischen den Kristallachsen bei einer Temperatur von 22°C von a = 16,368(5) Å, b = 16,301(3) Å, c = 18,408(5) Å, α = γ = 90° und β = 110,04(2)° gekennzeichnet ist.
• 28. Ein Verfahren zur Behandlung von bakteriellen und protozoischen Infektionen und entzündungsbedingten Krankheiten in menschlichen oder tierischen Individuen, umfassend die Verabreichung an einen Menschen oder ein Tier, der einer solchen Behandlung bedarf, die pharmazeutische Zubereitung, die das im Wesentlichen reine isostrukturelle Pseudopolymorph von 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A der Formel Ia, wie in Aspekt 25 ausgeführt, enthält.
• 29. Das Verfahren nach Aspekt 28, wobei das im Wesentlichen reine isostrukturelle Pseudopolymorph der Formel I aus der Gruppe der Pseudopolymorphe (Ia)-(Im) ausgewählt ist, die nachstehend ausgeführt sind, wobei x, y und S in Formel I und die durchschnittlichen Einheitszellenparameter, d.h. die Kristallachsenlängen a, b und c und die Winkel α, β und γ zwischen den Kristallachsen der kristallinen Struktur folgende sind: (Ia) x = 1, y = 0 und bei 22°C: a = 16,368(5) Å, b = 16,301(3) Å, c = 18,408(5) Å, α = γ = 90° und β = 110,04(2)°. (Ib) x = 1,25, y = 1 (S = MeOH) und bei 22°C: a = 16,546(3) Å, b = 16,185(6) Å, c = 18,511(7) Å, α = γ = 90° und β = 110,53(3)°. (Ic) x = 1, y = 0,5 (S = EtOH) und bei –173°C: a = 16,1400(10) Å, b = 16,1530(10) Å, c = 18,2640(10) Å, α = γ = 90° und β = 109,590(10)°. (Id) x = 1, y = 0,5 (S = n-PrOH) und bei 22°C: a = 16,32(2) Å, b = 16,344(16) Å, c = 18,610(18) Å, α = γ = 90° und β = 108,88(9)°. (Ie) x = 1,5, y = 0,5 (S = i-PrOH) und bei 22°C: a = 16,29410(10) Å, b = 16,24440(10) Å, c = 18,80600(10) Å, α = γ = 90° und β = 108,5701(3)°. (If) x = 1,5, y = 0,5 (S = n-BuOH) und bei –173°C: a = 16,1580(10) Å, b = 16,0190(10) Å, c = 18,4570(10) Å, α = γ = 90° und β = 108,866(10)°. (Ig) x = 1,25, y = 0,5 (S = i-BuOH) und bei 22°C: a = 16,166(8) Å, b = 16,123(4) Å, c = 18,591(14) Å, α = γ = 90° und β = 107,68(14)°. (Ih) x = 1, y = 0,5 (S = 1,2-Ethandiol) und bei 22°C: a = 16,232(15) Å, b = 16,213(10) Å, c = 18,531(9) Å, α = γ = 90° und β = 109,63(3)°. (Ii) x = 1, y = 0,5 (S = 1,3-Propandiol) und bei 22°C: a = 16,001(6) Å, b = 16,21(2) Å, c = 18,497(11) Å, α = γ = 90° und β = 109,20(6)°. (Ij) x = 1, y = 0,5 (S = Glycerin) und bei 22°C: a = 16,20(4) Å, b = 16,253(13) Å, c = 18,613(10) Å, α = γ = 90° und β = 109,30(5)°. (Ik) x = 1,5, y = 0,5 (S = Glycerin) und bei 22°C: a = 16,303(6) Å, b = 16,304(4) Å, c = 18,725(13) Å, α = γ = 90° und β = 108,968(15)°. (Il) x = 1,5, y = 0,5 (S = Aceton) und bei 22°C: a = 16,370(6) Å, b = 16,235(7) Å, c = 18,538(7) Å, α = γ = 90° und β = 109,09(3)°. (Im) x = 1, y = 0,5 (S = DMSO) und bei 22°C: a = 16,349(3) Å, b = 16,304(3) Å, c = 18,401(3) Å, α = γ = 90° und β = 108,948(12)°.
• 30. Das Verfahren nach Aspekt 29, wobei das im Wesentlichen reine isostrukturelle Pseudopolymorph die Strukturparameter x = 1, y = 0 besitzt und durch die monokline Raumgruppe P2₁ und die Einheitszellenparameter, d.h. die Kristallachsenlängen a, b und c und die Winkel α, β und γ zwischen den Kristallachsen bei einer Temperatur von 22°C von a = 16,368(5) Å, b = 16,301(3) Å, c = 18,408(5) Å, α = γ = 90° und β = 110,04(2)° gekennzeichnet ist.

The present invention also includes the following aspects:

• 1. A process for preparing a substantially pure isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A having the formula I:
  
  wherein S is an organic solvent that is at least partially miscible with water, x is 1, 1.25, 1.5 or 2, y is 0, 0.5 or 1, wherein the pseudopolymorph is represented by the monoclinic space group P2 ₁ , and the average unit cell parameter is characterized, comprising crystal axis lengths of a = 15.5-17.0 Å, b = 15.5-17.0 Å and c = 17.5-19.5 Å, and angles between the crystal axes of α = γ = 90 ° and β = 106 ° -112 °; the method comprising: (a) dissolving a 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A material in (1) an organic solvent which is at least partially water miscible, (2) a mixture of such organic Solvents, (3) a mixture of the organic solvent with water or (4) a mixture of water and at least one mineral or organic acid; (b) crystallizing the isostructural pseudopolymorph from the solution; (c) isolating the isostructural pseudopolymorph; and (d) transforming the isostructural pseudopolymorph of formula I into a stable isostructural pseudopolymorph of formula Ia wherein x = 1 and y = 0.
• 2. The process of aspect 1, wherein the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A material dissolved in step (a) is (i) a crystalline 9-deoxo-9a-aza-9a -methyl-9a-homoerythromycin A, either in crude or purified form, (ii) an amorphous 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, either in crude or purified form, (iii) solvates or hydrates of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, either in crude or in purified form, or (iv) a native solution of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, which is formed during the last step of his syntheses from one of his last intermediate stages.
• 3. The process of aspect 2, wherein the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A material used to prepare novel pseudopolymorphs, which is dissolved in step (a), is a crude 9-deo xo-9a-aza-9a-methyl-9a-homoerythromycin A in any of its known forms and having less than a pharmaceutically acceptable purity.
• 4. The method according to aspect 2, wherein the native solution of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A used in the preparation of novel pseudopolymorphs, which is dissolved in step (a), is a solution of 9- Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A is that formed in the native solution during the last step of its synthesis from one of its last intermediates.
• 5. The method of aspect 2, wherein the native solution of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A used to prepare new pseudopolymorphs, dissolved in step (a), is a solution of 9-deoxo-9a -aza-9a-methyl-9a-homoerythromycin A which is formed in the native solution during the last step of its synthesis from 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A as its last intermediate.
• 6. The process according to aspect 2, wherein the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dissolved in step (a) is in the form of a dispersion of 9-deoxo-9a-aza-9a-methyl-9a -homoerythromycin A and the 9-deoxo-9a-aza-9a-homoerythromycin A intermediate in the native solution present in the final stage of crude 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A synthesis is used.
• 7. The process of aspect 4, wherein the solvent in the native solution is selected from the group consisting of one or more haloalkanes having one or two carbon atoms, esters of acetic acid having a C ₂ -C ₄ lower alkyl group, monovalent C ₂ - C ₄ alkanols, C ₁ -C ₄ ketones, aromatic or substituted aromatic compounds or a mixture thereof.
• 8. The process according to aspect 2, wherein the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dissolved in step (a) is (a) amorphous 9-deoxo-9a-aza-9a-methyl- 9a-homoerythromycin A; a crystalline, anhydrous monohydrate, dihydrate or solvate form of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A or an isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of the formula I ,
• 9. The process of aspect 2, wherein the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dissolved in step (a) is of pharmaceutically acceptable purity.
• 10. The process of aspect 1, wherein step (a) is conducted at a temperature of about 20 ° C to about 100 ° C.
• 11. The process according to aspect 1, wherein the organic solvent in which the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dissolved in step (a) comprises one or more lower aliphatic straight-chain or branched alkanols, cycloalkanols, arylalkanols , Diols, triols, ethers, ketones, esters, amides, ureas, nitriles, sulfoxides or sulfones; one or more heterocyclic amines or lactams; or mixtures thereof.
• 12. A process according to aspect 1, wherein the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorph in step (b) is obtained by controlled cooling of the solution containing the 9-deoxo-9a-aza-9a methyl-9a-homoerythromycin A, crystallized at temperatures of about 80 ° C to about -10 ° C.
• 13. The process of aspect 1, wherein the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorph in step (b) is allowed to stand by standing or mixing at a temperature of about 25 to about 60 ° C the solution which is crystallized in step (a) in an organic solvent which is at least partially water-miscible under the stated isothermal conditions.
• 14. A process according to aspect 1, wherein the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A-pseudopolymorph is crystallized in step (b) at a temperature of about 25 to about 60 ° C by saturation of the solution, which is crystallized in step (a) in an organic solvent which is at least partially water-soluble with water until light turbidity of the solution.
• 15. The method according to aspect 1, wherein the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorph in step (b) is neutralized by the aqueous acidic solution of 9-deoxo-9a-aza-9a methyl-9a-homoerythromycin A formed in step (a) is crystallized at temperatures of about 80 to about -10 ° C.
• 16. The method of aspect 1, wherein the isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of formula I of the solution in step (b) in an amount of about 0.01 to about 5 , 0 wt .-%, based on the amount of the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A starting material is added to introduce crystallization nuclei of the isostructural Pseudopolymorphs.
• 17. The process of aspect 1, wherein the 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A pseudopolymorph of formula I is isolated in step (c) by: (i) separating the pseudopolymorph from that in step (a) formed solution; (ii) washing the resulting product with solvents (1), (2) or (3) used in step (a) at temperatures of about -10 to about 40 ° C; and (iii) drying the washed product under atmospheric pressure at temperatures of about 20 to about 120 ° C or under reduced pressures of about 2 kPa to about 80 kPa.
• 18. The method of aspect 1, wherein the pseudopolymorph of formula I in step (d) in the stable iso structural pseudopolymorph of formula Ia, wherein x = 1 and y = 0, by lyophilizing or further drying the pseudopolymorph at atmospheric pressure or at reduced pressures of from about 0.01 to about 80 kPa and temperatures from about -100 ° C to about 120 ° C is transferred.
• 19. The method according to aspect 1, wherein the pseudopolymorph of formula I (Ia: x = 1, y = 0) is formed in step (d) through the monoclinic space group P2 ₁ with the unit cell parameters at a temperature of 22 ° C is a = 16.368 (5) Å, b = 16.301 (3) Å, c = 18.408 (5) Å, α = γ = 90 °, and β = 110.04 (2) °.
• 20. The substantially pure isostructural pseudopolymorph of Formula I prepared by the method of Aspect 1.
• 21. The substantially pure isostructural pseudopolymorph of Formula Ia prepared by the method of Aspect 1, characterized by monoclinic space group P2 ₁ with the average unit cell parameters at a temperature of 22 ° C of a = 16.368 (5) Å, b = 16,301 (3) Å, c = 18,408 (5) Å, α = γ = 90 °, and β = 110.04 (2) °.
• 22. A substantially pure isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A having the formula I:
  
  wherein S is an organic solvent that is at least partially miscible with water, x is 1, 1.25, 1.5 or 2, y is 0, 0.5 or 1, wherein the pseudopolymorph is represented by the monoclinic space group P2 ₁ and the average unit cell parameters of crystal axis lengths of a = 15.5-17.0 Å, b = 15.5-17.0 Å and c = 17.5-19.5 Å, and angles between the crystal axes of α = γ = 90 ° and β = 106 ° -112 °.
• 23. The substantially pure isostructural pseudopolymorph of aspect 22 selected from the group of pseudopolymorphs (Ia) - (Im) set forth below, wherein x, y and S in formula I and the average unit cell parameters, ie the crystal axis lengths a, b and c and the angles α, β and γ between the crystal axes of the crystal structures, are: (Ia) x = 1, y = 0 and at 22 ° C: a = 16.368 (5) Å, b = 16.301 (3) Å, c = 18.408 (5) Å, α = γ = 90 ° and β = 110.04 (2) °. (Ib) x = 1.25, y = 1 (S = MeOH) and at 22 ° C: a = 16.546 (3) Å, b = 16.185 (6) Å, c = 18.511 (7) Å, α = γ = 90 ° and β = 110.53 (3) °. (Ic) x = 1, y = 0.5 (S = EtOH) and at -173 ° C: a = 16.1400 (10) Å, b = 16.1530 (10) Å, c = 18.2640 ( 10) Å, α = γ = 90 ° and β = 109.590 (10) °. (Id) x = 1, y = 0.5 (S = n-PrOH) and at 22 ° C: a = 16.32 (2) Å, b = 16.344 (16) Å, c = 18.610 (18) Å , α = γ = 90 ° and β = 108.88 (9) °. (Ie) x = 1.5, y = 0.5 (S = i-PrOH) and at 22 ° C: a = 16.29410 (10) Å, b = 16.24440 (10) Å, c = 18 , 80600 (10) Å, α = γ = 90 °, and β = 108.5701 (3) °. (If) x = 1.5, y = 0.5 (S = n-BuOH) and at -173 ° C: a = 16.1580 (10) Å, b = 16.0190 (10) Å, c = 18.4570 (10) Å, α = γ = 90 ° and β = 108.866 (10) °. (Ig) x = 1.25, y = 0.5 (S = i-BuOH) and at 22 ° C: a = 16.166 (8) Å, b = 16.123 (4) Å, c = 18.591 (14) Å , α = γ = 90 ° and β = 107.68 (14) °. (Ih) x = 1, y = 0.5 (S = 1,2-ethanediol) and at 22 ° C: a = 16,232 (15) Å, b = 16,213 (10) Å, c = 18,531 (9) Å , α = γ = 90 ° and β = 109.63 (3) °. (Ii) x = 1, y = 0.5 (S = 1,3-propanediol) and at 22 ° C: a = 16,001 (6) Å, b = 16,21 (2) Å, c = 18,497 (11 ) Å, α = γ = 90 ° and β = 109.20 (6) °. (Ij) x = 1, y = 0.5 (S = glycerol) and at 22 ° C: a = 16.20 (4) Å, b = 16.253 (13) Å, c = 18.613 (10) Å, α = γ = 90 ° and β = 109.30 (5) °. (Ik) x = 1.5, y = 0.5 (S = glycerol) and at 22 ° C: a = 16.303 (6) Å, b = 16.304 (4) Å, c = 18.725 (13) Å, α = γ = 90 ° and β = 108.968 (15) °. (Il) x = 1.5, y = 0.5 (S = acetone) and at 22 ° C: a = 16.370 (6) Å, b = 16.235 (7) Å, c = 18.538 (7) Å, α = γ = 90 ° and β = 109.09 (3) °. (Im) x = 1, y = 0.5 (S = DMSO) and at 22 ° C: a = 16.349 (3) Å, b = 16,304 (3) Å, c = 18,401 (3) Å, α = γ = 90 ° and β = 108.948 (12) °.
• 24. The essentially pure isostructural pseudopolymorph according to aspect 22 having the structural parameters: x = 1, y = 0 and the monoclinic space group P2 ₁ and the unit cell parameters, ie the crystal axis lengths a, b and c and the angles α, β and γ between the crystal axes at a temperature of 22 ° C of a = 16.368 (5) Å, b = 16.301 (3) Å, c = 18.408 (5) Å, α = γ = 90 ° and β = 110.04 (2 ) °.
• 25. A pharmaceutical preparation comprising a substantially pure isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of the formula I:
  
  wherein S is an organic solvent that is at least partially miscible with water x is 1, 1.25, 1.5 or 2, y is 0, 0.5 or 1, wherein the pseudopolymorph is represented by the monoclinic space group P2 ₁ and the average Unit cell parameters of crystal axis lengths of a = 15.5-17.0 Å, b = 15.5-17.0 Å and c = 17.5-19.5 Å and angles between the crystal axes of α = γ = 90 ° and β = 106 ° -112 ° in combination with a pharmaceutically acceptable carrier.
• 26. The pharmaceutical preparation according to aspect 25, wherein the substantially pure isostructural pseudopolymorph of formula I from the group of pseudopolymorphs (Ia) - (Im), which are listed below, is selected, wherein x, y and S in formula I and the mean unit cell parameters, ie the crystal axis lengths a, b and c and the angles α, β and γ between the crystal axes of the crystalline structures, are: (Ia) x = 1, y = 0 and at 22 ° C: a = 16.368 ( 5) Å, b = 16.301 (3) Å, c = 18.408 (5) Å, α = γ = 90 ° and β = 110.04 (2) °. (Ib) x = 1.25, y = 1 (S = MeOH) and at 22 ° C: a = 16.546 (3) Å, b = 16.185 (6) Å, c = 18.511 (7) Å, α = γ = 90 ° and β = 110.53 (3) °. (Ic) x = 1, y = 0.5 (S = EtOH) and at -173 ° C: a = 16.1400 (10) Å, b = 16.1530 (10) Å, c = 18.2640 ( 10) Å, α = γ = 90 ° and β = 109.590 (10) °. (Id) x = 1, y = 0.5 (S = n-PrOH) and at 22 ° C: a = 16.32 (2) Å, b = 16.344 (16) Å, c = 18.610 (18) Å , α = γ = 90 ° and β = 108.88 (9) °. (Ie) x = 1.5, y = 0.5 (S = i-PrOH) and at 22 ° C: a = 16.29410 (10) Å, b = 16.24440 (10) Å, c = 18 , 80600 (10) Å, α = γ = 90 ° and β = 108.5701 (3) °. (If) x = 1.5, y = 0.5 (S = n-BuOH) and at -173 ° C: a = 16.1580 (10) Å, b = 16.0190 (10) Å, c = 18.4570 (10) Å, α = γ = 90 ° and β = 108.866 (10) °. (Ig) x = 1.25, y = 0.5 (S = i-BuOH) and at 22 ° C: a = 16.166 (8) Å, b = 16.123 (4) Å, c = 18.591 (14) Å , α = γ = 90 ° and β = 107.68 (14) °. (Ih) x = 1, y = 0.5 (S = 1,2-ethanediol) and at 22 ° C: a = 16,232 (15) Å, b = 16,213 (10) Å, c = 18.531 (9) Å, α = γ = 90 °, and β = 109.63 (3) °. (Ii) x = 1, y = 0.5 (S = 1,3-propanediol) and at 22 ° C: a = 16,001 (6) Å, b = 16,21 (2) Å, c = 18,497 (11 ) Å, α = γ = 90 ° and β = 109.20 (6) °. (Ij) x = 1, y = 0.5 (S = glycerol) and at 22 ° C: a = 16.20 (4) Å, b = 16.253 (13) Å, c = 18.613 (10) Å, α = γ = 90 ° and β = 109.30 (5) °. (Ik) x = 1.5, y = 0.5 (S = glycerol) and at 22 ° C: a = 16.303 (6) Å, b = 16.304 (4) Å, c = 18.725 (13) Å, α = γ = 90 ° and β = 108.968 (15) °. (Il) x = 1.5, y = 0.5 (S = acetone) and at 22 ° C: a = 16.370 (6) Å, b = 16.235 (7) Å, c = 18.538 (7) Å, α = γ = 90 ° and β = 109.09 (3) °. (Im) x = 1, y = 0.5 (S = DMSO) and at 22 ° C: a = 16.349 (3) Å, b = 16,304 (3) Å, c = 18,401 (3) Å, α = γ = 90 ° and β = 108.948 (12) °.
• 27. The pharmaceutical preparation according to aspect 25, wherein the substantially pure isostructural pseudopolymorph has the structural parameters: x = 1, y = 0 and the monoclinic space group P2 ₁ and the unit cell parameters, ie the crystal axis lengths a, b and c and the angles α , β and γ between the crystal axes at a temperature of 22 ° C of a = 16,368 (5) Å, b = 16,301 (3) Å, c = 18,408 (5) Å, α = γ = 90 ° and β = 110, 04 (2) ° is marked.
• 28. A method of treating bacterial and protozoan infections and inflammatory diseases in human or animal individuals, comprising administering to a human or animal in need of such treatment, the pharmaceutical preparation containing the substantially pure isostructural pseudopolymorph of 9- Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of formula Ia as set forth in aspect 25.
• 29. The method of aspect 28, wherein the substantially pure isostructural pseudopolymorph of formula I is selected from the group of pseudopolymorphs (Ia) - (Im) set forth below wherein x, y and S in formula I and the average Unit cell parameters, ie the crystal axis lengths a, b and c and the angles α, β and γ between the crystal axes of the crystalline structure are: (Ia) x = 1, y = 0 and at 22 ° C: a = 16.368 (5) Å, b = 16.301 (3) Å, c = 18.408 (5) Å, α = γ = 90 ° and β = 110.04 (2) °. (Ib) x = 1.25, y = 1 (S = MeOH) and at 22 ° C: a = 16.546 (3) Å, b = 16.185 (6) Å, c = 18.511 (7) Å, α = γ = 90 ° and β = 110.53 (3) °. (Ic) x = 1, y = 0.5 (S = EtOH) and at -173 ° C: a = 16.1400 (10) Å, b = 16.1530 (10) Å, c = 18.2640 ( 10) Å, α = γ = 90 ° and β = 109.590 (10) °. (Id) x = 1, y = 0.5 (S = n-PrOH) and at 22 ° C: a = 16.32 (2) Å, b = 16.344 (16) Å, c = 18.610 (18) Å , α = γ = 90 ° and β = 108.88 (9) °. (Ie) x = 1.5, y = 0.5 (S = i-PrOH) and at 22 ° C: a = 16.29410 (10) Å, b = 16.24440 (10) Å, c = 18 , 80600 (10) Å, α = γ = 90 ° and β = 108.5701 (3) °. (If) x = 1.5, y = 0.5 (S = n-BuOH) and at -173 ° C: a = 16.1580 (10) Å, b = 16.0190 (10) Å, c = 18.4570 (10) Å, α = γ = 90 ° and β = 108.866 (10) °. (Ig) x = 1.25, y = 0.5 (S = i-BuOH) and at 22 ° C: a = 16.166 (8) Å, b = 16.123 (4) Å, c = 18.591 (14) Å , α = γ = 90 ° and β = 107.68 (14) °. (Ih) x = 1, y = 0.5 (S = 1,2-ethanediol) and at 22 ° C: a = 16,232 (15) Å, b = 16,213 (10) Å, c = 18,531 (9) Å , α = γ = 90 ° and β = 109.63 (3) °. (Ii) x = 1, y = 0.5 (S = 1,3-propanediol) and at 22 ° C: a = 16,001 (6) Å, b = 16,21 (2) Å, c = 18,497 (11 ) Å, α = γ = 90 ° and β = 109.20 (6) °. (Ij) x = 1, y = 0.5 (S = glycerol) and at 22 ° C: a = 16.20 (4) Å, b = 16.253 (13) Å, c = 18.613 (10) Å, α = γ = 90 ° and β = 109.30 (5) °. (Ik) x = 1.5, y = 0.5 (S = glycerol) and at 22 ° C: a = 16.303 (6) Å, b = 16.304 (4) Å, c = 18.725 (13) Å, α = γ = 90 ° and β = 108.968 (15) °. (Il) x = 1.5, y = 0.5 (S = acetone) and at 22 ° C: a = 16.370 (6) Å, b = 16.235 (7) Å, c = 18.538 (7) Å, α = γ = 90 ° and β = 109.09 (3) °. (Im) x = 1, y = 0.5 (S = DMSO) and at 22 ° C: a = 16.349 (3) Å, b = 16,304 (3) Å, c = 18,401 (3) Å, α = γ = 90 ° and β = 108.948 (12) °.
• 30. The method of aspect 29, wherein the substantially pure isostructural pseudopolymorph has the structural parameters x = 1, y = 0 and the monoclinic space group P2 ₁ and the unit cell parameters, ie the crystal axis lengths a, b and c and the angles α, β and γ between the crystal axes at a temperature of 22 ° C of a = 16.368 (5) Å, b = 16.301 (3) Å, c = 18.408 (5) Å, α = γ = 90 ° and β = 110.04 ( 2) ° is marked.

Claims (7)

Substantially pure isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A having the formula Ia:

wherein S is an organic solvent that is at least partially miscible with water, and y is 0 and x 1 and wherein the pseudopolymorph is represented by the monoclinic space group P2 ₁ , and the average unit cell parameters comprising the crystal axis lengths of a = 15.5-17.0 Å, b = 15.5-17.0 Å and c = 17.5 19.5 Å and the angles between the crystal axes of α = γ = 90 ° and β = 106 ° -112 °. Essentially pure isostructural pseudopolymorph according to claim 1, wherein the average unit cell parameters, the crystal axis lengths a, b and c and the angles α, β and γ between the crystal axes of the crystal structures at 22 ° C are the following: a = 16.368 (5) Å, b = 16,301 (3) Å, c = 18.408 (5) Å, α = γ = 90 ° and β = 110.04 (2) °, in which the data in brackets the statistical variation of the last digit specify the specified parameter. Essentially pure isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A according to either claim 1 or 2, which does not exceed 10% of one contains another compound. Essentially pure isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A according to claim 3 containing not more than 10% of another crystalline one or amorphous form of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A contains. Essentially pure isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A according to claim 3 containing not more than 5% of another compound contains. Essentially pure isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A according to claim 4 containing not more than 5% of another crystalline one or amorphous form of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A contains. Pharmaceutical preparation, which is a substantially pure isostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, as claimed in any one of the claims to 6, in combination with a pharmaceutically acceptable carrier includes.