Reaxys_NDF_Azithromycin

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Query

Query Results Date

1. Query

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51 reactions 2011-04-19 08h:55m:34s (EST)

Search as: Product, As drawn, No salts, No mixtures


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Rx-ID: 23057466 View in ReaxysYield Conditions & References

87 % Example Name 1CExample 1C; Preparation of Azithromycin dihydrate; To the 300 ml of acetone, 100 gm 9-Deoxo-9a-aza-9a-homoery-thromycin A (prepared according to Example IB) was added. The mixture of 17.49 ml of formic acid and 17.49 ml offormaldehyde was EPO <DP n="14"/>prepared. This mixture was added to 9-Deoxo-9a-aza-9a-homoerythromycin Asolution within 5 to 6 hours at 40.deg. C. The reaction was monitored for 2 hours at 40.deg. to 45.deg. C. The pH ofthe reaction mixture was adjusted to 11 to 11.5 by adding sodium hydroxide solution. The charcoal treatment was givento reaction mixture. The acetone layer was separated from the reaction mixture. To the acetone layer, 650 ml waterwas added within 12 hour while stirring. The mixture was stirred at 20.deg. C for 12 hours. After the completion ofreaction, Azithromycin dihydrate was filtered and washed with water. Azithromycin dihydrate was dried at 65.deg. C.The yield and purity of the Azithromycin dihydrate was 87 percent and 98 percent.

Stage 1: With formic acid in acetone, Time= 7 - 8h, T= 40 - 45 °CStage 2: With sodium hydroxide in water, acetone, pH= 11 - 11.5

Patent; KOPRAN RESEARCH LABORATORIES LTD; WO2007/15265; (2007); (A2) EnglishView in Reaxys

77 % Example Name 56.48 g of a compound of formula III obtained according to example 4 are dissolved in 58 ml of ethyl acetate and 0.6 mlof formic acid and 1.30 ml of 37percent aqueous formaldehyde are added to the solution obtained. The mixture obtainedis refluxed for ca. 2 hours. HPLC analysis shows the formation of azithromycin. [00106] Yield: 77percent.of theory.

With formic acid in water, ethyl acetate, Time= 2h, Heating / reflux

Patent; Biochemie S.A.; US6703372; (2004); (B1) EnglishView in Reaxys

71 % With formic acid in chloroform, water, Time= 2h, T= 70 °C , Inert atmosphere, Eschweiler-Clarke reaction

Glansdorp, Freija G.; Spandl, Richard J.; Spring, David R.; Swatton, Jane E.; Welch, Martin; Loiseleur, Olivier;Organic and Biomolecular Chemistry; vol. 6; nb. 22; (2008); p. 4120 - 4124View in Reaxys

Example Title Example - Preparation of azithromycin MonohydrateExample - Preparation of azithromycin Monohydrate9-Deoxo-9a-aza-9a-homoerythromycin A (73.5g - 0.1 mole) was dissolved in 250 ml acetonitrile..To this solution, formic acid (19 ml, 0.5 mole) followed by formaldehyde (37percent, 20 ml, 0.25 mole) were added andrefluxed for 24 hours..The PH of the reaction mixture was adjusted with alkali (NaOH solution) to 10.5 and filtered to remove particles..To the filtered acetonitrile solution, an equal volume of water was added to precipitate azithromycin monohydrate ascube shaped crystals..The crystals were filtered and dried under vacuum at 50.deg.C to give 65g of azithromycin monohydrate having watercontent of 5percent (water content measured by the Karl Fischer titration method)..This sample of azithromycin monohydrate crystals has a characteristic solid state (KBr pellet) IR spectrum (Fig 1) anda characteristic X-ray diffraction pattern (Fig 2).In the process described above reductive methylation is carried out in acetonitrile (solvent) and Azithromycin mono-hydrate crystals are directly precipitated from the reaction mixture without the need for conducting any extraction pro-cedure.All patent, patent applications, articles, publications, textbooks and any other references cited in this application areincorporated herein by reference in their entirety for all purposes.

http://www.reaxys.com/reaxys/secured/hopinto.do?context=R&query=RX.ID=23057466&ln=

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Stage 1: With formic acid in water, acetonitrile, Time= 24h, Heating / refluxStage 2: With sodium hydroxide in water, acetonitrile, pH= 10.5

Patent; Alembic Limited; EP1400528; (2004); (A1) EnglishView in Reaxys

Example Name 2Example Title Preparation of Crude AzithromycinAzaerythromycin (100 kg) (Ercros Ind., Madrid, Spain) and 95percent ethanol (500 L) were combined to form a mixturein a 1,000-L reaction vessel.The mixture was then stirred.Paraformaldehyde (10.4 kg) and formic acid (15 kg) were added, and the mixture was heated at a reflux temperature(i.e., 78.deg. C.) for about 4 hours.When thin-layer chromatography (TLC) indicated the disappearance of azaerythromycin, about 200 L of ethanol wasremoved by distillation under vacuum.At about 25-30.deg. C., water (300 kg) and 25percent ammonium hydroxide (40 kg) were added to bring the pH toabove 9.Then, more water (300 kg) was added.The mixture was further stirred at room temperature for about 6 hours.The precipitate was filtered and washed with water, providing about 105 kg of crude, wet azithromycin (contained24.74percent water (w/w)).

With formic acid in ethanol, Time= 4h, T= 78 °C , Industry scale

Patent; Gutman, Daniella; Shahal, Leah; US2006/63725; (2006); (A1) EnglishView in Reaxys

Example Name 2.2(b); The pH of the chloroform extract was adjusted to 5.0 to 5.5 with formic acid (17.0 g) and formaldehyde (17.0 g)and the resultant mixture was refluxed for 10 hr. After completion of the reaction, water (500 ml) was added and pHbrought to 4.0 with hydrochloric acid. The pH of the reaction mixture was adjusted to 8.0 using sodium hydroxide solutionand the aqueous layer was extracted with chloroform. The chloroform extract was concentrated to dryness. The residueobtained was dissolved <n="13"/>in methylene chloride (750.0 ml), filtered and concentrated ana dried under reducedpressure. The solid so obtained was dissolved in acetonitrile (750.0 ml). The acetonitrile was partially distilled out (600.0ml) under vaccum. The slurry obtained was cooled to 10-25.deg.C and filtered to get anhydrous azithromycin. Yield:45.0 g. Purity: 99.0 percent.

Stage 1: With formic acid in chloroform, Time= 10h, pH= 5 - 5.5, Heating / refluxStage 2: With hydrogenchloride in water, pH= 4Stage 3: With sodium hydroxide, pH= 8, Product distribution / selectivity

Patent; WOCKHARDT LTD; PUROHIT, Manish; MUKARRAM, Siddiqui Mohammad Jaweed; NAITHANI, PankajKumar; POKALWAR, Raj Kumar; SUTARIYA, Prakash Maganlal; WO2007/80507; (2007); (A2) EnglishView in Reaxys

Example Name 4Example 4: Preparation of azithromycin; The Cyclic amine of formula III obtained from example 1, was dissolved inchloroform (1 Litre) and adjusted to pH 5.0 to 5.5 with methylating mixture i.e. formic acid (17.0 g) and formaldehyde(17.0 g) and refluxed for 10 hr. The resultant mass was subjected to process as exemplified in example 3 (b), to getthe title compound.

With formic acid in chloroform, Time= 10h, pH= 5 - 5.5, Heating / reflux, Product distribution / selectivity


Example Name 3Example-3; [100][101] Preparation of Azithromycin; [102][103] 9-Deoxo-9a-aza-9a-homoerythromycin A (III) (73.5g)was dissolved in acetone(250ml). To this solution formic acid (19ml) followed by formaldehyde (37percent, 20ml) wereadded and refluxed for 24 hrs. The pH of the reaction mixture was adjusted with alkali to 10.5 and filtered to removeparticles. To the filtered acetone solution equal volume of water was added to precipitate azithromycin (IV). The crystalswere filtered and dried under vacuum at 5O0C to give the title product (65g).






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Stage 1: With formic acid in acetone, Time= 24h, RefluxStage 2: in acetone, pH= 10.5, Alkaline solution

Patent; ALEMBIC LIMITED; WO2009/156938; (2009); (A2) EnglishView in Reaxys

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87 % Example Name 1CTo the 300 ml of acetone, 100 gm 9-Deoxo-9a-aza-9a-homoerythromycin A (prepared according to Example IB) wasadded. The mixture of 17.49 ml of formic acid and 17.49 ml of formaldehyde was prepared. This mixture was added to9-Deoxo-9a-aza-9a-homoerythromycin A solution within 5 to 6 hours at 40.deg. C. The reaction was monitored for 2hours at 40.deg. to 45.deg. C. The pH of the reaction mixture was adjusted to 11 to 11.5 by adding sodium hydroxidesolution. The charcoal treatment was given to reaction mixture. The acetone layer was separated from the reactionmixture. To the acetone layer, 650 ml water was added within 12 hour while stirring. The mixture was stirred at 20.deg.C for 12 hours. After the completion of reaction, Azithromycin dihydrate was filtered and washed with water. Azithro-mycin dihydrate was dried at 65.deg. C. The yield and purity of the Azithromycin dihydrate was 87 percent and 98percent.

Stage 1: With formic acid in acetone, Time= 7 - 8h, T= 40 - 45 °CStage 2: With sodium hydroxide in water, acetone, pH= 11 - 11.5Stage 3: With water in acetone, Time= 24h, T= 20 °C


76.7 % Example Name 1; 2100g (0. 136G moles) of azaerythromycin A was dissolved in 300ML of acetone under stirring at room temperature.Formic acid (85percent, 15.6g, 0. 288G moles) and formaldehyde solution (37percent, 14. 10G, 0. 1737G moles) wereadded and resulting mixture was heated at 50- 55C for 8 hrs. The mixture was then cooled to room temperature andstirred with 16ML of 30percent aqueous NAOH solution. The aqueous layer was separated and acetone layer containingmaterial was filtered through polishing filter and the clear filtrate was heated to 38 to 40C. The first portion of water(70ML) was added to this in about 1 hr maintaining a temperature of 38 to 40C followed by stirring for 2hrs at the sametemperature to allow abundant formation of crystals. The second portion of water (380ML) was then added in about 2hrs and thereafter maintained for 8-10 hrs at 38-40C. The resulting crystals were cooled to 10 to 15C, maintained for2hrs and recovered by filtration. The crystals were washed with 50ML X 2 of chilled water and dried under vacuum at45 to 50C till constant weight furnishing 80gms of azithromycin dihydrate in 80percent w/w yield from azaerythromycinA (74.9percent of theoretical) with a moisture content of 4. 7percent. EXAMPLE 2 Example 1 was repeated except thatthe second portion of water used in the CRYSTALLIZATION PROCESS CONTAINED LOML OF LIQ. ammonia (i. e.370MLOFWATER+ 10MLOFLIQ. ammonia). Thus, 82g of azithromycin dihydrate was obtained in 82percent w/w yieldfrom azaerythromycin A (76.7percent of theoretical).

Stage 1: With formic acid in water, acetone, Time= 8h, T= 20 - 55 °CStage 2: With water in acetone, Time= 10 - 12h, T= 38 - 40 °CStage 3: With water

Patent; JUBILANT ORGANOSYS LIMITED; WO2005/3144; (2005); (A1) EnglishView in Reaxys

73 - 74.9 % Example Name 3; 4; 5; 6EXAMPLE 3 100g (0.136g moles) of azaerythromycin A was dissolved in 400mL of chloroform under stirring at roomtemperature. Formic acid (85percent, 15.6g, 0. 288G. moles) and formaldehyde solution (37percent, 14. 10G, 0. 1737G






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moles) were added and the resulting mixture was heated at 50-55C for 10HRS. The mixture was then cooled to roomtemperature and washed with 25ML X 2 of 10percent aq. NAOH solution. The chloroform layer was separated, driedover anhydrous magnesium sulphate and distilled off completely under reduced pressure till dryness. This was furtherchased with 100mL of acetone till dryness. The residual product was cooled to room temperature and dissolved in300ML of acetone and the resulting solution was filtered through polishing filter and crystallization was carried out asper the procedure given in Example 1 to get 78g of azithromycin dihydrate in 78percent. w/w from azaerythromycin A(73percent of theoretical). EXAMPLE 4 The procedure described in Example 3 was repeated but using methylenedichloride as a solvent during the reaction (20 hrs/reflux conditions) to furnish 80g of azithromycin dihydrate in 80percentw/w yield from azaerythromycin A (74.9percent of theoretical). EXAMPLE 5 100g (0. 136G moles) of azaerythromycinA was dissolved in 400mL of chloroform under stirring at room temperature. Formic acid (85percent, 15.6g, 0.288g.moles) and formaldehyde solution (37percent, 14. 10G, 0. 1737G moles) were added and the resulting mixture washeated at 50-55C for 10hrs. The mixture was then cooled to room temperature and washed with 25mL X 2 of 10percentaq. NAOH solution. The chloroform layer was separated. Mixture of Hydrochloric acid and water (20ML Con HC1 +380ML water) added to the chloroform layer, stir for 15 minutes and separate the aqueous layer. The aqueous layerwas washed with 200 ml chloroform. The aqueous layer cool to 25-30C and adjust the aqueous layer pH to 9. 5-10.00by using 30percent aqueous NAOH solution. The resulting solid was extracted with chloroform. The chloroform layerwas washed with 100 ml water. Chloroform layer dried over anhydrous magnesium sulphate and distilled off completelyunder reduced pressure till dryness. This was further chased with 100mL of acetone till dryness. The residual productwas cooled to room temperature and dissolved in 300mL of acetone and the resulting solution was filtered throughpolishing filter and crystallization was carried out as per the procedure given in Example 1 to get 78g of azithromycindihydrate in 78percent w/w from azaerythromycin A (73percent of theoretical). EXAMPLE 6 The procedure describedin Example 5 was repeated but using methylene dichloride as a solvent during the reaction (20 hrs/reflux conditions)to furnish 80g of azithromycin dihydrate in 80percent w/w yield from azaerythromycin A (74.9percent of theoretical).SCHEME H H HO OH H3 H3 Ho OH CH3 CH3 0 0 H3C"\\CH3 H3C OCH3 'cl CH3 + H (|) H3 9-deoxo-9a-aza-9a-homoerythromycin (azaerythromycin A) Step-1 Formic acid I Formaldehyde CH \\ 3 \\\\cl 3 \\ OH OH v H3C/. H3c",//0OCH3 1 CH3 wCH3 \\o OH Single () ) Step (Current Hygroscopic azithromycin monohydrate (= Azithromycin Crude)invention) Step-2 Crystallization cl HgC-\\CH \\ W 3C/t CH3 C ? XCH3 OH QH 3 H3c,/, \\, \\CH 3 OH , g3 C/ss, u I I OH3 CH3 H CH3 CH3 H Ici 3 Non-hygroscopic azithromycin dihydrate

Stage 1: With formic acid in chloroform, water, Time= 10 - 20h, T= 20 - 55 °C , Heating / refluxStage 2: With water in acetone, Time= 10 - 12h, T= 38 - 40 °C

Patent; JUBILANT ORGANOSYS LIMITED; WO2005/3144; (2005); (A1) EnglishView in Reaxys

O OH O

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95 % Example Name 2Example Title EXAMPLE 2; Preparation of crystalline azithromycin monohydrate100 [G] of crystalline 9a-deoxo-9a-aza-9a-homoerythromycin A obtained as described in the preceding example, 9.2[G] of [PARAFORMALDEHYDE,] 44.9 ml of triethylamine and 603 ml of isopropyl acetate are fed into a 2 litre reactorequipped with a mechanical stirrer, condenser and thermometer. The mixture is then brought to [50.deg.C] and 12.2[ML] of formic acid are added. The heterogeneous mixture is heated to [70.deg.C] and maintained under these condi-tions for 4 hours, at the end of which it is cooled to ambient temperature and 320 [ML] of de-ionised water are addedto the mixture, which is treated with 12.8 ml of 30 sodium hydroxide. The phases are separated and the aqueous phaseis again extracted with 192 ml of isopropyl acetate. The pooled organic extracts are then evaporated to dryness andredissolved in 225 mi of absolute ethanol. 675 ml of deionised water are slowly added to the solution obtained, whichis brought to [50.deg.C,] observing the progressive turbidity of the mixture, which over time gives rise to a suspensionof crystalline material. The mixture is maintained at [20-25.deg.C] for 4 hours, then filtered and washed with 130 ml ofdeionised water. The crystalline solid is discharged and dried at [40.deg.C] for 12 hours under a residual pressure of40 mm Hg. The dry solid consisting of crystalline azithromycin weighs 96.1 g (yield 95percent). The spectroscopic data




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[(IR,] NMR, XRD) and the spectrum confirm that this is crystalline azithromycin monohydrate. TLC and HPLC analysesconfirm that the azithromycin monohydrate obtained in this example presents a greater purity than the correspondingproduct in monohydrate form obtained as described in [USP4,] 474, 768.

With triethylamine in isopropanol acetate, Time= 4h, T= 70 °C , Eschweiler-Clarke Reaction

Patent; Chemi SpA; WO2003/102009; (2003); (A1) EnglishView in Reaxys

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93 % Example Name 1.BMethod B37.5g of azithromycin anhydrate (50mmol, moisture content 0.2percent) was dissolved in 400ml of anhydrous2-propanol, and 13.4g of L-malic acid (lOOmmol) was added thereto, followed by stirring the resulting solution overnight at room temperature, and then, for 2 hours at 0 to 5 C . The 0 precipitate formed was filtered, washed with cold2-propanol, and dried at 45 C , to obtain 47.3 g of the title compound (yield: 93percent) as a white crystal.M.P.: 182-184CSpecific rotation, [?]D20: -32.8 (c=l, methanol) 5 Moisture content (Karl-Fisher titrator): 0.4percent or less (after dry-ing)IR (KBr, cm"1): 3415, 3057, 2980, 2932, 2884, 1736, 1607, 1462, 1386, 1326, 1177, 1084, 106O5 1000, 939, 895,726, 637.The azithromycin L-malate compound obtained above was subjected 0 to X-ray diffraction analysis, and theresult showed that it had a crystal structure having major peaks of 1/I0 values of at least 10percent at 20=1=0.2 of 6.0,10.0, 11.0, 11.4, 12.5, 13.9, 15.5, 16.2, 17.3, 18.0, 19.2, 20.0, 20.5, 20.8, 21.2, 22.6, 24.5, 25.7. Its anhydrate form wasconfirmed by the result of moisture content measurement. 5 The azithromycin L-malate anhydrate thus obtained wasexposed at40 C and 75percent relative humidity for 10 hours, and found that its moisture content is increased by about2.0percent. That is, the azithromycin L-malate anhydrate was converted into a hydrate form thereof.

in isopropyl alcohol, T= 0 - 20 °C

Patent; HANMI PHARM. CO., LTD.; WO2006/132486; (2006); (A1) EnglishView in Reaxys

90 % Example Name 1Example Title Preparation of Azithromycin L-Malate Monohydrate from L-Malic Acid100.0 g of azithromycin dihydrate (127 mmol) was dissolved in 1,000 ml of 95percent 2-propanol, and 34.1 g. of L-malicacid (254 mmol) having an optical purity of 99.7percent ee was added thereto, followed by stirring the resulting solutionovernight at room temperature and then for 2 hours at 0 to 5.deg. C. The precipitate formed was filtered, washed withcold 2-propanol, and dried at 45.deg. C., to obtain 118.3 g of the title compound (yield: 90percent) as a white crys-tal.M.P.: 173175.deg. C.Specific rotation, [α]D 20: -32.8.deg. (c=1, methanol)Moisture content (Karl-Fisher titrator):1.80percent (calculated for monohydrate, 1.74percent)Optical purity of malic acid after salt formation (HPLC): 99.9per-cent ee of L-malic acidAzithromycin relative content (HPLC): 74.6percent (calculated for one molecule, 72.35percent)L-malic acid relative content (0.1N KOH titration): 25.8percent (calculated for two molecules, 25.91percent)IR (KBr,cm-1): 3411, 3059, 2971, 1742, 1716, 1619, 1594, 1493, 1457, 1345, 1286, 1177, 1112, 1080, 1056, 1013, 1001, 900,773, 637The X-ray powder diffraction spectrum of the crystalline azithromycin L-malate monohydrate obtained (FIG.1) show that the azithromycin L-malate monohydrate is a crystal having distinctively characteristic main peaks (thosehaving I/I0 and d values of at least 10percent).

in water, isopropyl alcohol, T= 0 - 20 °C , Product distribution / selectivity

Patent; Hanmi Pharm Co., Ltd; US2009/318375; (2009); (A1) EnglishView in Reaxys






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89 % With tetrabutyl ammonium fluoride in tetrahydrofuran, Time= 5h, T= 20 °C , Inert atmosphere

Kim, Hyoung Cheul; Kang, Sung Ho; Angewandte Chemie, International Edition; vol. 48; nb. 10; (2009); p. 1827 -1829View in Reaxys

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Example Name 6EXAMPLE 6 [00107] 70.0 g of azithromycin dihydrate are dissolved in 280 ml of methyl acetate at 25.deg.. The resultingsolution is heated to 55-60.deg. and 225 ml of methyl acetate are distilled off. the distillation residue is cooled to 20.deg..Azithromycin in the form of a monohydrate crystallizes, is filtrated off and dried. [00108] Yield: 47.5 g. Water content:2.5percent

in methyl acetate, T= 20 - 60 °C


Example Name 7EXAMPLE 7 [00109] 15.0 g of azithromycin dihydrate are dissolved in 75 ml of acetone, anhydrous sodium sulphateis added, the mixture obtained is stirred for ca. 10 minutes and the solid is filtrated off and washed with 15 ml of acetone.From the solution obtained 57 ml of acetone are distilled off and the resulting suspension is cooled to room temperature.Azithromycin in the form of a monohydrate crystallizes, is filtrated off and dried. [00110] Yield: 7.3 g. Water content:2.6percent

With sodium sulfate in acetone, Time= 0.166667h


Example Name 10EXAMPLE 10 [00115] 20 g of azithromycin in the form of a dihydrate, suspended in 40 ml of water are treated with 2NHCl. A solution is obtained, is filtered and the filtrate is added dropwise to 80 ml of water keeping the pH between 10and 11 by addition of 0.5 N sodium hydroxide at a temperature of ca. 55.deg.. The suspension obtained is cooled toroom temperature and stirred for ca. 30 minutes. A solid precipitate obtained is filtrated off, washed with water and







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dried. 18.2 g of azithromycin in the form of a monohydrate are obtained. Water content: 3.7percent. Residual solvent:acetone 0.01percent. [00116] Azithromycin assay on anhydrous basis (HPLC): 98.6percent.

Stage 1: With hydrogenchloride in waterStage 2: With sodium hydroxide in water, Time= 0.5h, T= 20 - 55 °C , pH= 10 - 11


Example Name 8EXAMPLE 8 [00111] 10.0 g of azithromycin dihydrate are suspended in 10 ml of absolute ethanol and the mixture isheated. A clear solution is obtained, which is cooled slowly to room temperature and stirred at ca. 25.deg. for ca. onehour. Azithromycin in the form of a monohydrate crystallizes. Ethanol is evaporated off and azithromycin in the form ofa monohydrate is filtrated off and dried. [00112] Yield: 5.26 g. Water content: 1.9percent

in ethanol, Time= 1h, T= 20 °C


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78 % Example Name 3Reference Example 3: Preparation of azithromycin DL-malate anhydrate10.0g of azithromycin dihydrate (12.7mmol)was dissolved in 100mL of anhydrous 2-propanol, and 3.4 Ig of DL-malic acid (25.4mmol, an optical purity of 1.7percentee in favor of L-malic acid) was added thereto, followed by stirring over night at room temperature, and then, for 2 hoursat 0 to 5 C . The precipitate formed was filtered, washed with cold 2-propanol, and dried in a 40 C oven, to obtain 10.3g of the title compound (yield: 78percent) as a white crystalline powder.M.P.: 169~172 CSpecific rotation, [?]D : -35.5(c=l, methanol) Optical purity of malic acid (HPLC): 3.4percent ee of L-malic acid Moisture content (Karl-Fisher titrator):0.5percent or less (after drying) IR (KBr, cm"1): 3410, 2973, 2937, 2882, 1736, 1603, 1458, 1385, 1170, 1076, 1060,1016, 1008, 895, 641The azithromycin DL-malate compound obtained above was subjected to X-ray diffraction anal-ysis, which showed a crystal structure having major peaks (1/I0 values of at least 10percent) at 2?+-0.2 of 5.9, 9.9,10.9, 11.3, 12.4, 16.0, 17.2, 17.9, 19.9, 20.6, 22.5, 24.4. It was also shown to an anhydrate form by the measurementof moisture content. However, its moisture content is increased to 6percent or higher when exposed at 40 C and75percent relative humidity for 10 hours.Meanwhile, instead of the azithromycin DL-malate anhydrate 0 obtained above,the non-hygroscopic azithromycin L-malate monohydrate was crystallized under the aqueous solvent condition, asshown in Example 8.








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79 % Example Name 2Example 2: Preparation of azithromycin D-malate anhydrate 10.Og of azithromycin dihydrate (12.7mmol) was dissolvedin 100mL of anhydrous 2-propanol, and 3.4 Ig of D-malic acid (25.4mmol) having an optical purity of 98.2percent eewas added thereto, followed by stirring over night at room temperature, and then, for 2 hours at 0 to 5 C . The precipitateformed was filtered, washed with cold 2-propanol, and dried at 45 C5 to obtain 10.4 g of the title compound (yield:79percent) as a white crystal.M.P.: 160-163 CSpecific rotation, [?]25: -39.5 (c=l, methanol) Optical purity of D-malicacid after salt formation (HPLC): 98.9percent ee Moisture content (Karl-Fisher titrator): 0.4percent or less (after drying)IR (KBr5 cm'1): 3427, 2974, 2937, 2882, 1735, 1598, 1466, 1385, 1179, 1171, 1080, 1060, 1013, 1002, 899, 726.Theazithromycin D-malate compound obtained above was subjected to X-ray diffraction analysis, and the result showedthat it had a crystal structure showing major peaks (1/I0 values of at least 10percent) at 2?+-0.2 of 5.7, 9.9, 10.9, 11.3,12.3, 15.9, 17.1, 17.8, 18.2, 19.9, 20.6, 22.2. Its anhydrate form was confirmed by the result of moisture content meas-urement. However, it showed an increase of moisture content of 8percent or higher when exposed at 40 C and 75per-cent relative humidity for 10 hours.The azithromycin D-malate anhydrate obtained above did not convert to a hydrateform under the aqueous solvent condition employed in Examples 1 to 8.



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OH

HO 2


78 % Example Name 3Example Title Preparation of Azithromycin DL-Malate Anhydrate10.0 g of azithromycin dihydrate (12.7 mmol) was dissolved in 100 ml of anhydrous 2-propanol, and 3.41 g of DL-malicacid (25.4 mmol, an optical purity of 1.7percent ee in favor of L-malic acid) was added thereto, followed by stirring overnight at room temperature, and then, for 2 hours at 0 to 5.deg. C. The precipitate formed was filtered, washed with cold2-propanol, and dried in a 40.deg. C. oven, to obtain 10.3 g of the title compound (yield: 78percent) as a white crystallinepowder.M.P.: 169172.deg. C.Specific rotation, [α]D 25: -35.5.deg. (c=1, methanol)Optical purity of malic acid (HPLC):3.4percent ee of L-malic acidMoisture content (Karl-Fisher titrator): 0.5percent or less (after drying)IR (KBr, cm-1): 3410,2973, 2937, 2882, 1736, 1603, 1458, 1385, 1170, 1076, 1060, 1016, 1008, 895, 641The azithromycin DL-malate com-pound obtained above was subjected to X-ray diffraction analysis, which showed a crystal structure having major peaks(I/Io values of at least 10percent) at 2ψ+/-0.2 of 5.9, 9.9, 10.9, 11.3, 12.4, 16.0, 17.2, 17.9, 19.9, 20.6, 22.5, 24.4. It wasalso shown to an anhydrate form by the measurement of moisture content. However, its moisture content is increasedto 6percent or higher when exposed at 40.deg. C. and 75percent relative humidity for 10 hours.






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OH

OH O

OH

O

H O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH OH

OH

O

HO

O O

HO

O

O

HO

O

O

O

N

N

O

HO

OH

HO 2


79 % Example Name 2Example Title Preparation of Azithromycin D-Malate Anhydrate10.0 g of azithromycin dihydrate (12.7 mmol) was dissolved in 100 ml of anhydrous 2-propanol, and 3.41 g of D-malicacid (25.4 mmol) having an optical purity of 98.2percent ee was added thereto, followed by stirring over night at roomtemperature, and then, for 2 hours at 0 to 5.deg. C. The precipitate formed was filtered, washed with cold 2-propanol,and dried at 45.deg. C., to obtain 10.4 g of the title compound (yield: 79percent) as a white crystal.M.P.: 160163.deg.C.Specific rotation, [α]D 25: -39.5.deg. (c=1, methanol)Optical purity of D-malic acid after salt formation (HPLC):98.9percent eeMoisture content (Karl-Fisher titrator): 0.4percent or less (after drying)IR (KBr, cm-): 3427, 2974, 2937,2882, 1735, 1598, 1466, 1385, 1179, 1171, 1080, 1060, 1013, 1002, 899, 726.The azithromycin D-malate compoundobtained above was subjected to X-ray diffraction analysis, and the result showed that it had a crystal structure showingmajor peaks (I/Io values of at least 10percent) at 2ψ+/-0.2 of 5.7, 9.9, 10.9, 11.3, 12.3, 15.9, 17.1, 17.8, 18.2, 19.9, 20.6,22.2. Its anhydrate form was confirmed by the result of moisture content measurement. However, it showed an increaseof moisture content of 8percent or higher when exposed at 40.deg. C. and 75percent relative humidity for 10 hours.



O

OH

O

O

HO

O

O

O

HN N

O

HO

OH

OH

O

OH

O O

OH O

O

O

N

N

O

HO

OH

OH

O H H


Example Name 1Example Title Hygroscopic Azithromycin MonohydratePREPARATION 1Hygroscopic Azithromycin MonohydrateSubstantially following the methylation procedure of Kobrehel et al., U.S. Patent 4,517,359; and the crystallizationprocedure of Bright, U.S. Patent 4,474,768; 9-deoxo-9a-aza-9a-homoerythromycin A (previously called 11-aza-10-deoxo-10-dihydroerythromycin A; 100 g, 0.218 mol) was dissolved with stirring in 400 ml CHCl3.Formic acid (98percent; 10.4 ml, 0.436 mol) and formaldehyde (37percent; 16.4 ml, 0.349 mol) were added over 4-5minutes, and the mixture heated at reflux for 20 hours.The mixture was cooled to ambient temperature, diluted with 400 ml H2O and adjusted to pH 10.5 with 50percent NaOH.The aqueous layer was separated and extracted 2 x 100 ml with fresh CHCl3.






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The organic layers were combined, stripped in vacuo to 350 ml, twice diluted with 450 ml of ethanol and restripped to350 ml, and finally diluted with 1000 ml H2O over a 1 hour period, pausing for 15 minutes as a slurry began to developafter the addition of about 250 ml of H2O.Title product was recovered by filtration and dried in air at 50.deg.C for 24 hours, 85 g; mp 136.deg.C; differentialthermal analysis (heating rate 20.deg.C/minute) shows an endotherm at 142.deg.C; thermal gravimetric analysis (heat-ing rate 30.deg.c/minute) shows a 2.6percent weight loss at 100.deg.C and a 4.5percent weight loss at 150.deg.C;water content 3.92percent; ethanol content 1.09percent.Anal. Calcd. for C3 8H7 2N2O1 2 (corrected for ethanol and water content):C, 58.46; H, 9.78; N, 3.74; Alkoxy, 4.67.Found: C, 58.40; H, 9.29; N, 3.50; Alkoxy, 4.52.

With formaldehyd, formic acid in ethanol, chloroform, water

Patent; PFIZER INC.; EP307128; (1989); (A2) EnglishView in Reaxys

Example Name 1Example Title Hygroscopic Azithromycin MonohydratePREPARATION 1Hygroscopic Azithromycin MonohydrateSubstantially following the methylation procedure of Kobrehel et al., U.S. Pat. No.4,517,359; and the crystallization procedure of Bright, U.S. Pat. No. 4,474,768; 9-deoxo-9a-aza-9a-homoerythromycinA (previously called 11-aza-10-deoxo-10-dihydroerythromycin A; 100 g, 0.218 mol) was dissolved with stirring in 400ml CHCl3.Formic acid (98percent; 10.4 ml, 0.436 mol) and formaldehyde (37percent; 16.4 ml, 0.349 mol) were added over 4-5minutes, and the mixture heated at reflux for 20 hours.The mixture was cooled to ambient temperature, diluted with 400 ml H2O and adjusted to pH 10.5 with 50percent NaOH.The aqueous layer was separated and extracted 2*100 ml with fresh CHCl3.The organic layers were combined, stripped in vacuo to 350 ml, twice diluted with 450 ml of ethanol and restripped to350 ml, and finally diluted with 1000 ml H2O over a 1 hour period, pausing for 15 minutes as a slurry began to developafter the addition of about 250 ml of H2O.Title product was recovered by filtration and dried in air at 50.deg. C. for 24 hours, 85 g; mp 136.deg. C.; differentialthermal analysis (heating rate 20.deg. C./minute) shows an endotherm at 142.deg. C.; thermal gravimetric analysis(heating rate 30.deg. C./minute) shows a 2.6percent weight loss at 100.deg. C. and a 4.5percent weight loss at 150.deg.C.; water content 3.92percent; ethanol content 1.09percent.Anal. Calcd. for C38H72N2O12 (corrected for ethanol and water content): C, 58.46; H, 9.78; N, 3.74; Alkoxy, 4.67. Found:C, 58.40; H, 9.29; N, 3.50; Alkoxy, 4.52.

With formaldehyd, formic acid in ethanol, chloroform, water

Patent; Pfizer Inc.; US6268489; (2001); (B1) EnglishView in Reaxys

O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH

O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH

H

H

H 2 O


Example Name 4.AExample Title Example 4; Preparation of the Orthorhombic Pseudopolymorph of Formula Id (S = cyclohexane); (MethodA)





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Crude 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (5.0 g, having a water content of 5.7percent) was dissolvedin 55 ml cyclohexane at a temperature of [70.deg.C.] The solution was treated with actived carbon, filtered, and cooledto room temperature over a period of 2 hours. The precipitated crystals were allowed to stand at room temperature fora further 15 hours. The crystals were isolated and dried at atmospheric pressure and room temperature to constantweight. The product was 4.7 g of the orthorhombic isostructural pseudopolymorph of Formula Id (S = cyclohexane).The water content was 2.35 percent, and the cyclohexane content was 7.9percent. Upon single x-ray diffraction anal-ysis, the orthorhombic pseudopolymorph was characterized as identified in Table 1 and Figure 5.

With water, T= 70 °C

Patent; PLIVA, d.d.; WO2004/9608; (2004); (A2) EnglishView in Reaxys

Example Name 8.DExample Title Example 8; Preparation of Orthorhombic Pseudopolymorph of the Formula Id (S = cyclohexane); (MethodD)Amorphous 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (5.0 g, having a water content of 3.8percent) was dis-solved in 55 ml cyclohexane with stirring at a temperature of [40.deg.C.] n-hexane was gradually added stepwise atthis temperature, with stirring until slight turbidity formed. The solution was then gradually cooled to room temperatureover 5 hours and allowed to stand at this temperature, without stirring, for a further 18 hours. The resulting precipitatewas a crystalline orthorhombic isostructural pseudopolymorph of the Formula Id (S = cyclohexane). The precipitatewas filtered, washed with a minimum amount of cold 10percent v/v cyclohexane solution in n-hexane, and dried atatmospheric pressure and room temperature to constant weight. 4.9 g of the pseudopolymorph Id, analogous to thatprepared in Example 4, was thus produced

With water in hexane, T= 40 - 50 °C


Example Name 7.CExample Title Example 7; Preparation of Orthorhombic Isostructural Pseudopolymorph of Formula Id (S = cyclohex-ane); (Method C)Amorphous 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (5.0 g, having a water content of 3.8percent) was add-ed to [55ML] cyclohexane. The mixture was heated to [40-50.deg.C] with stirring. The solution was treated with activatedcarbon, filtered, and cooled to a temperature of [15.deg.C] over a period of 2 hours. The mixture was seeded with theisostructural pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A of Formula Id (S = cyclohexane)and cooled stepwise to [0.deg.C] with stirring over a 24 hour period. The precipitate thus formed was the crystallineisostructural pseudopolymorph Id in the form of the cyclohexane solvate (S=cyclohexane). The precipitate was filtered,washed with a minimum amount of cold cyclohexane and dried to constant weight at atmospheric pressure and roomtemperature. 4.7 g of the pseudopolymorph Id, analogous to that prepared in Example 4 was thus produced.

With water, T= 40 - 50 °C


O O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH O O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH

H

H

H 2 O


Example Name 3.A






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Example Title Example 3; Preparation of the Orthorhombic Pseudopolymorph of Formula Ic (S= Methyl tert-butyl ether);(Method A)Crude 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (10.0 g, having a water content of 5.7percent) was dissolvedin 45 ml methyl tert-butyl ether (MTBE) at a temperature of [50.deg.C.] The solution was treated with actived carbon,filtered, and cooled to room temperature over a period of 2 hours. The precipitated crystals were allowed to stand atroom temperature for a further 15 hours. The crystals were isolated and dried at atmospheric pressure and roomtemperature to constant weight. The product was 8.8g of the orthorhombic isostructural pseudopolymorph of generalFormula Ic (S = methyl tert-butyl ether). The water content was 2.4percent, and the MTBE content was 7.9percent.Upon single x-ray diffraction analysis, the orthorhombic pseudopolymorph was characterized as identified in Table 1and Figure 4.



Example Name 9.DExample Title Example 9; Preparation of Pseudopolymorph of Formula Ic (S = methyl tert-butanol ether); (Method D)9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate (5.0 g, purity: USP 25) was dissolved in 54 ml methyltert-butyl ether. The stirred solution was heated to [30-40.deg.C,] and subsequently added gradually over a period of2 hours to 70 ml hexane at [40.deg.C,] under seeding with 250 mg of the orthorhombic isostructural pseudopolymorphof the general Formula Ic (S = methyl tert-butyl ether). The mixture was then gradually cooled to-10.deg.C over 24hours. The thus precipitated crystalline orthorhombic isostructural pseudopolymorph of the general formula Ic (S =methyl tert-butyl ether) was filtered, washed with a minimum amount of cold methyl tert-butyl ether, and dried at at-mospheric pressure and room temperature to constant weight. 7.8 g of the pseudopolymorph Ic, analogous to thatprepared in Example 3, was thus obtained.

With water in hexane, Time= 2h, T= 30 - 40 °C


O O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH

H

H

H 2 O

O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH


100 % Example Name 11Example Title Example 11The orthorhombic pseudopolymorph of the general Formula Ic (S = methyl tert- butyl ether) obtained according toExample 3, was dried at a temperature of [80.deg.C,] under a reduced pressure of 2 kPa to constant weight. The yieldof the stable amorphous 9-deoxo-9a- aza-9a-methyl-9a-homoerythromycin A thus obtained was quantitative; purity:according to USP 25. A powder diffractogram and scanning electron microscopy (SEM) image of the stable amorphousproduct thus obtained are set forth in Figures 6 and 7, respectively.

, T= 80 °C , p= 15.0015Torr







14/55 2011-04-19 08:56:52

OH

OH

O

OH

O O

HO

O

O

HO

O

O

O

N

N

O

HO

OH

HO 2

OH

OH

O

OH

O O

HO

O

O

HO

O

O

O

N

N

O

HO

OH

HO

H 2 O

2


85 % Example Name 7Example 7: Preparation of azithromycin L-malate monohvdrate from azithromycin L-malate anhydrateo 50.Og of azi-thromycin L-malate anhydrate (moisture content 0.4percent) was dissolved in 400 ml of 95percent 2-propanol bywarming, and the resulting solution was stirred overnight at room temperature and then for 2 hours at 0 to 5 C . Theprecipitate formed was filtered, washed with cold 2-propanol, and dried at 45 C, to obtain 43.1 g of the title compound(yield: 85percent) as a 5 white crystal.M.P.: 173-175 CMoisture content (Karl-Fisher titrator): 1.83percent (calculatedfor monohydrate, 1.74percent) o The XPRD and IR absorption spectrum results of the compounds obtained were thesame as those of Example 1.

With water in isopropyl alcohol, T= 0 - 20 °C , Product distribution / selectivity


O

O

O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH

O

O O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH

H

H

H 2 O


Example Name 1.AExample Title Preparation of the Orthorhombic [PSEUDOPOLYMORPHS]; Example 1; Preparation of the Orthorhom-bic Pseudopolymorph of Formula la (S=1, 4-dioxane); (Method A)Crude 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (10.0 g, having a water content of 5.7percent) was dissolvedin 20 ml dioxane at a temperature of [80.deg.C.] The solution was treated with actived carbon, filtered, and cooled toroom temperature over a period of 3 hours. The precipitated crystals were allowed to stand at room temperature foranother 15 hours. The crystals were isolated and dried at atmospheric pressure and room temperature to constantweight. The product was 3.8g of a crystalline orthorhombic isostructural pseudopolymorph of Formula la in the form ofa 1,4-dioxane solvate (S = 1,4-dioxane). The water content (determined by KF titration), was 2.54percent and the 1,4-dioxane content (determined by GC) was 10.5percent. Upon single crystal X-ray diffraction analysis, the orthorhombicpseudopolymorph was characterized as identified in Table 1 and Figure 2.



Example Name 10.EExample Title Example 10; Preparation of Orthorhombic Pseudopolymorph of Formula Ia (S [= 1,] 4 dioxane) from aNative Solution of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A; (Method E)60 ml of a native solution of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A in ethyl acetate, prepared as describedin WO 01/00640, was diluted with a further 40 ml of ethyl acetate. The resulting mixture was alkalized with 10percent






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[NAOH] solution to a pH value of 9.8, and the layers separated. The ethyl acetate layer was washed with a saturatedsodium chloride solution, and treated with activated carbon. The mixture was filtered and the carbon remaining on thefilter was washed with 5 [ML] ethyl acetate. To the combined ethyl acetate solution (both the filtrate and wash) 10 ml1,4-dioxane was added. The ethyl acetate was distilled out at atmospheric pressure. The residue after distillation wasslowly cooled from [100.deg.C] to [30.deg.C] over a period of 5 hours. The resulting precipitate was a crystalline iso-structural pseudopolymorph of the general Formula la (S = 1,4-dioxane). The precipitate was filtered, washed with aminimum amount of cold aqueous 1,4-dioxane solution (10percent v/v) and dried at atmospheric pressure and roomtemperature to constant weight. 1.9 g of the pseudopolymorph [IA,] analogous to that prepared in Example 1, wasobtained.

Stage 1: With sodium hydroxide, water in ethyl acetate, pH= 9.8Stage 2: in ethyl acetate


O H H

O

OH

O

O

HO

O

O

O

HN N

O

HO

OH

OH

O

OH

O O

OH O

O

O

N

N

O

HO

OH

OH

O H H


Example Name 1Example Title Hygroscopic Azithromycin MonohydratePREPARATION 1Hygroscopic Azithromycin MonohydrateSubstantially following the methylation procedure of Kobrehel et al., U.S. Pat. No.4,517,359; and the crystallization procedure of Bright, U.S. Pat. No. 4,474,768; 9-deoxo-9a-aza-9a-homoerythromycinA (previously called 11-aza-10-deoxo-10-dihydroerythromycin A; 100 g, 0.218 mol) was dissolved with stirring in 400ml CHCl3.Formic acid (98percent; 10.4 ml, 0.436 mol) and formaldehyde (37percent; 16.4 ml, 0.349 mol) were added over 4-5minutes, and the mixture heated at reflux for 20 hours.The mixture was cooled to ambient temperature, diluted with 400 ml H2 O and adjusted to pH 10.5 with 50percentNaOH.The aqueous layer was separated and extracted 2*100 ml with fresh CHCl3.The organic layers were combined, stripped in vacuo to 350 ml, twice diluted with 450 ml of ethanol and restripped to350 ml, and finally diluted with 1000 ml H2 O over a 1 hour period, pausing for 15 minutes as a slurry began to developafter the addition of about 250 ml of H2 O.Title product was recovered by filtration and dried in air at 50.deg. C. for 24 hours, 85 g; mp 136.deg. C.; differentialthermal analysis (heating rate 20.deg. C./minute) shows an endotherm at 142.deg. C.; thermal gravimetric analysis(heating rate 30.deg. C./minute) shows a 2.6percent weight loss at 100.deg. C. and a 4.5percent weight loss at 150.deg.C.; water content 3.92percent; ethanol content 1.09percent.Anal. Calcd. for C38 H72 N2 O12 (corrected for ethanol and water content):C, 58.46; H, 9.78; N, 3.74; Alkoxy, 4.67. Found: C, 58.40; H, 9.29; N, 3.50; Alkoxy, 4.52.

With formaldehyd, formic acid in ethanol, chloroform

Patent; Pfizer Inc.; US4963531; (1990); (A1) EnglishView in Reaxys





16/55 2011-04-19 08:56:52

OH

HO

O OH

O H O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH

OH

OH

O

OH

O O

HO

O

O

HO

O

O

O

N

N

O

HO

OH

HO

H 2 O

2


87 % Example Name 2Examples 2 to 6: Preparation of azithromycin L-malate monohydrate from L-malic acidThe procedure of Example 1was repeated except that azithromycin, L-malic acid and the solvent as shown in Table 3 were used, to obtain the titlecompound. Table 3

With water in isopropyl alcohol, T= 0 - 20 °C , Product distribution / selectivity


O HO

O

O

OH

O

O O

N

N

O

HO

OH

HO O HO

O

O

OH

O

O O

N

N

O

HO

OH

HO

O H

H 2


84.2 % With water in acetone, Time= 24h, Ambient temperature

Bayod-Jasanada, Miguel; Carbajo, Rodrigo J.; Lopez-Ortiz, Fernando; Journal of Organic Chemistry; vol. 62; nb.21; (1997); p. 7479 - 7481View in Reaxys

O

O

O

B (v3)

N

HO

O

O

HO O

O

O

O

OH

OH

N

O HO

O

O

OH

O

O O

N

N

O

HO

OH

HO


70.5 % With sulfuric acid in water, acetonitrile, Time= 0.5h, T= 15 °C , pH 2









17/55 2011-04-19 08:56:52

HO

HO

O OH O

OH

O O

OH

O

O

HO

O

O O

N N

O

HO

OH

OH HO

OH O

HO

O

OH O

O OH

O

O

HO

O

O

O

N

N

O

HO

OH

HO H

H


Example Name 1Example Title Example 1. Preparation of azithromycin hydrogen citrate20g of azithromycin are added to 100ML of acetone (water content according to Karl-Fisher of 1 to 5percent), the mixtureis stirred at ambient temperature until dissolved. 5.35g of citric acid are added and the mixture is heated at reflux. It isthen cooled to 0-5.deg.C, filtered, washed with acetone and dried under vacuum at 40.deg.C to yield 22.4g of azithro-mycin hydrogen citrate (water content according to Karl-Fisher of 1. 2percent and acetone content less than 0.5percent).The azithromycin content determined by HPLC is 80percent and the citric acid content by electrometric titration is20percent, corresponding to the stoichiometric ratio of the azithromycin hydrogen citrate. The salt can contain up to8percent water depending on the drying method (by vacuum, fluidised bed, static), but is preferably 6percent, underrelative humidity conditions of 40percent. Figures 1,2 and 3 show the X-ray diffraction spectrum, the carbon 13 nuclearmagnetic resonance spectrum (13C-NMR) in solid state and the IR spectrum, recorded on KBr tablet, respectively.

in acetone, Heating / reflux

Patent; QUIMICA SINTETICA, S.A.; WO2004/106355; (2004); (A1) EnglishView in Reaxys

Example Name 2Example Title Example 2. Preparation of azithromycin hydrogen citrate20g of azithromycin dihydrate and 3.5g of citric acid monohydrate are added to 50 ml of methyl acetate. This is heatedat reflux, cooled to ambient temperature, filtered, washed with methyl acetate and dried under vacuum at 40.deg.C.Figures 4,5, and 6 show the X-ray diffraction spectrum, the carbon 13 nuclear magnetic resonance spectrum (13C-NMR) in solid state and the IR spectrum, recorded on KBr tablet, respectively.

in methyl acetate, Heating / reflux


Example Name 3Example Title Example 3. Preparation of azithromycin hydrogen citrateFollowing the procedure set out in example 2 and replacing the methyl acetate by tetrahydrofuran, azithromycin hy-drogen citrate is obtained. Figures 7,8 and 9 show the X-ray diffraction spectrum, the carbon 13 nuclear magneticresonance spectrum (13C-NMR) in solid state and the IR spectrum, recorded on KBr tablet, respectively.

in tetrahydrofuran, Heating / reflux







18/55 2011-04-19 08:56:52

O OH

O

O

HO

O

O

O

N

N

O

HO

OH

OH

O H

H

1.5

O

OH

O O

OH O

O

O

N

N

O

HO

OH

OH

O H H

2


57 - 100 % Example Name 2To evaluate a proposed excipient, the active dose of the azithromycin was suspended with the desired amount ofpotential excipient in a 0.1 M phosphate buffer system adjusted to a pH of 8.16. The buffer system was created bydissolving 13.738 g of NaH2PO4*H2O in 900 ml of water, adjusting the pH to 8.16 with sodium hydroxide, and dilutingthe solution to 1 liter with water. The sample, once constituted with buffer, was then stored at room temperature for thedesired constituted product shelf-life. The azithromycin product was then isolated through filtration, and the resultingsolid filtrate analyzed by a Solid-State Nuclear Magnetic Resonance method described previously that allows for quan-titation of the dihydrate form present. The effect of various individual flavoring components and of sucrose upon con-version of azithromycin form G to azithromycin dihydrate (form A), in suspensions, were evaluated as follows. An 820mg dose of form G azithromycin was weighed and mixed with 200 mg of each flavoring or sucrose. The mass of eachflavoring, used in this test, was chosen to match that of the anticipated required amount for effective flavoring in theconstituted POS. In this example, five flavorings, specifically artificial creme de vanilla, BC banana, Trusil banana, Trusilcherry and artificial grape were investigated in addition to sucrose. Each of the binary samples were then constitutedwith 18 mls of pH=8.16 buffer and stored for 1, 5 and 10-days at room temperature. A control suspension of azithromycinform G constituted with 18 mls of pH=8.16 buffer was run with each series of experiments using the same storageconditions. Upon completion of the constituted storage time period these samples were filtered to isolate drug productand analyzed using the SS-NMR method to quantify the amount of azithromycin dihydrate present. The results of thesestudies are provided in the following Table 3. [Table 3.] Effect of Flavorings and Sucrose On Conversion of AzithromycinForm G to Form A) FormulationsConstituted 1 day (Δ percentForm A)Constituted 5 days (Δ percentForm A)Constituted10 days (Δ percentForm A)Artificial Creme de Vanilla Flavor0percent4percent30percentBC Banana Flavor0per-cent27percentACTrusil Banana Flavor32percent57percentACSucrose2percent1percent6percentTrusil Cherry Fla-vor32percent75percentACArtificial Grape Flavor57percent75percentAC AC means all converted to form A As shownpreviously in Example 1, azithromycin form G, in combination with only water, experienced significant conversion toform A over the 10-day constitution interval. Further, when combined with a flavoring, such as Artificial Creme de vanilla,artificial grape, Trusil cherry, BC banana or Trusil banana, the rate of conversion substantially increased. Thus, thistest shows that these five flavorings need to be stabilized for use in oral suspension formulations of azithromycin formG with a 5-10 day constituted shelf-life. However, suspensions with Artificial Creme de vanilla and BC banana flavoringsdid not exhibit conversion to azithromycin dihydrate (form A) during the first day after constitution. Further, the presenceof sucrose, without flavoring, appears to have stabilized the azithromycin form G in a constituted suspension such thatonly minimal conversion to form A was observed over the 10-day period. This example demonstrated a simple methodfor choosing suitable excipients for non-dihydrate azithromycin oral suspensions that will minimize form conversion.

With Artifical Grape Flavour, water, Time= 24 - 240h, T= 20 °C , pH= 8.16, Aqueous phosphate buffer, Conversion ofstarting material

Patent; Pfizer Products Inc.; EP1498141; (2005); (A1) EnglishView in Reaxys

32 - 100 % Example Name 2To evaluate a proposed excipient, the active dose of the azithromycin was suspended with the desired amount ofpotential excipient in a 0.1 M phosphate buffer system adjusted to a pH of 8.16. The buffer system was created bydissolving 13.738 g of NaH2PO4*H2O in 900 ml of water, adjusting the pH to 8.16 with sodium hydroxide, and dilutingthe solution to 1 liter with water. The sample, once constituted with buffer, was then stored at room temperature for thedesired constituted product shelf-life. The azithromycin product was then isolated through filtration, and the resultingsolid filtrate analyzed by a Solid-State Nuclear Magnetic Resonance method described previously that allows for quan-titation of the dihydrate form present. The effect of various individual flavoring components and of sucrose upon con-version of azithromycin form G to azithromycin dihydrate (form A), in suspensions, were evaluated as follows. An 820mg dose of form G azithromycin was weighed and mixed with 200 mg of each flavoring or sucrose. The mass of each




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flavoring, used in this test, was chosen to match that of the anticipated required amount for effective flavoring in theconstituted POS. In this example, five flavorings, specifically artificial creme de vanilla, BC banana, Trusil banana, Trusilcherry and artificial grape were investigated in addition to sucrose. Each of the binary samples were then constitutedwith 18 mls of pH=8.16 buffer and stored for 1, 5 and 10-days at room temperature. A control suspension of azithromycinform G constituted with 18 mls of pH=8.16 buffer was run with each series of experiments using the same storageconditions. Upon completion of the constituted storage time period these samples were filtered to isolate drug productand analyzed using the SS-NMR method to quantify the amount of azithromycin dihydrate present. The results of thesestudies are provided in the following Table 3. [Table 3.] Effect of Flavorings and Sucrose On Conversion of AzithromycinForm G to Form A) FormulationsConstituted 1 day (Δ percentForm A)Constituted 5 days (Δ percentForm A)Constituted10 days (Δ percentForm A)Artificial Creme de Vanilla Flavor0percent4percent30percentBC Banana Flavor0per-cent27percentACTrusil Banana Flavor32percent57percentACSucrose2percent1percent6percentTrusil Cherry Fla-vor32percent75percentACArtificial Grape Flavor57percent75percentAC AC means all converted to form A As shownpreviously in Example 1, azithromycin form G, in combination with only water, experienced significant conversion toform A over the 10-day constitution interval. Further, when combined with a flavoring, such as Artificial Creme de vanilla,artificial grape, Trusil cherry, BC banana or Trusil banana, the rate of conversion substantially increased. Thus, thistest shows that these five flavorings need to be stabilized for use in oral suspension formulations of azithromycin formG with a 5-10 day constituted shelf-life. However, suspensions with Artificial Creme de vanilla and BC banana flavoringsdid not exhibit conversion to azithromycin dihydrate (form A) during the first day after constitution. Further, the presenceof sucrose, without flavoring, appears to have stabilized the azithromycin form G in a constituted suspension such thatonly minimal conversion to form A was observed over the 10-day period. This example demonstrated a simple methodfor choosing suitable excipients for non-dihydrate azithromycin oral suspensions that will minimize form conversion.

With Trusil Banana Flavour, water, Time= 24 - 240h, T= 20 °C , pH= 8.16, Aqueous phosphate buffer, Conversion ofstarting material



With Trusil Cherry Flavour, water, Time= 24 - 240h, T= 20 °C , pH= 8.16, Aqueous phosphate buffer, Conversion ofstarting material



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13 % Example Name 3The data showed that both the sucrose and vanilla flavorings contain only trace amounts of volatile organics that couldresult in the azithromycin form conversion. This correlated well to the lower conversion rate of these two formulationcomponents. The Trusil cherry and banana flavorings, however, appeared to have significant amounts of volatile or-ganics that may be responsible for the greater conversion enhancing behavior of these excipients. Standards of theseidentified solvent components were then used to investigate the source of the stability problem introduced by theseflavorings. The estimated concentration of each solvent in a constituted POS was calculated based on the GC-MSquantification of the specified solvent in the flavorings. Aqueous solutions of each solvent/component were then createdat these concentrations and 18 mls of each solvent-solution was used to constitute an unflavored POS formulation Isample using form G. The constituted drug suspensions were stored at room temperature for 24-hours, before beingfiltered and analyzed by SS-NMR for quantification of azithromycin form change over this interval. POS formulations Iand II were constituted with 18 mls of water and stored identically to serve as controls for this experiment. The resultsof this investigation can be seen in Table 8, below. [Table 8.] Effects of Flavoring Components Upon Azithromycin FormG Conversion Form G POS FormulationConstitution Medium (18 mL)percentForm AFormulation IIWater71FormulationIWater0Formulation I0.197 mg/ml ethyl acetate0Formulation I0.002 mg/ml ethyl ester propanoic acid0FormulationI0.025 mg/ml 3-methyl-1-butanol0Formulation I0.815 mg/ml 3-methyl-butyl acetate2Formulation I0.144 mg/ml 2-meth-yl-butyl acetate0Formulation I0.587 mg/ml benzaldehyde0Formulation I0.043 mg/ml isoamyl isovalerate13FormulationI0.785 mg/ml 3-methyl-butyl acetate + 0.562 mg/ml benzaldehyde11 When constituted with water, form G azithromycinin POS formulation II demonstrated approximately 71percent conversion to azithromycin dihydrate. POS formulation Iwhich is POS formulation II without the cherry, Trusil banana and vanilla flavorings, had no conversion to the azithro-mycin dihydrate when constituted with water. The constitution of POS formulation I with 3-methyl-butyl acetate andisoamyl isovalerate solutions, instead of water, exhibited an increased conversion to azithromycin dihydrate. As a resultof this observation it is evident that an azithromycin POS formulation will be more stable if the levels of these organiccomponents are minimized, or absent from the constituted POS all together. Flavorings should be chosen which donot contain these organic components for optimal POS stability. Furthermore, the stability of a constituted POS for-mulation can be improved by substituting flavorings that contain small amounts of these organic components for thosein the formulation that have large amounts of these organic components. It was also demonstrated that these organiccomponents may not enhance the conversion in an independent manner. Combinations of organic components, asdemonstrated through constitution with a 0.785 mg/ml 3-methyl-butyl acetate and 0.562 mg/ml benzaldehyde solution,may also interact to further facilitate the formation of the dihydrate species as compared to the effect of individualisolated components. For this reason it is beneficial not only to avoid such combinations of components through carefulflavoring choices, but also to choose flavorings with the least amount of organic components in order to minimize theprobability of observing such a phenomenon.

With iso-pentyl iso-pentanoate, water, Time= 24h, T= 20 °C , Conversion of starting material


11 % Example Name 3The data showed that both the sucrose and vanilla flavorings contain only trace amounts of volatile organics that couldresult in the azithromycin form conversion. This correlated well to the lower conversion rate of these two formulationcomponents. The Trusil cherry and banana flavorings, however, appeared to have significant amounts of volatile or-ganics that may be responsible for the greater conversion enhancing behavior of these excipients. Standards of theseidentified solvent components were then used to investigate the source of the stability problem introduced by theseflavorings. The estimated concentration of each solvent in a constituted POS was calculated based on the GC-MSquantification of the specified solvent in the flavorings. Aqueous solutions of each solvent/component were then createdat these concentrations and 18 mls of each solvent-solution was used to constitute an unflavored POS formulation Isample using form G. The constituted drug suspensions were stored at room temperature for 24-hours, before beingfiltered and analyzed by SS-NMR for quantification of azithromycin form change over this interval. POS formulations Iand II were constituted with 18 mls of water and stored identically to serve as controls for this experiment. The resultsof this investigation can be seen in Table 8, below. [Table 8.] Effects of Flavoring Components Upon Azithromycin FormG Conversion Form G POS FormulationConstitution Medium (18 mL)percentForm AFormulation IIWater71FormulationIWater0Formulation I0.197 mg/ml ethyl acetate0Formulation I0.002 mg/ml ethyl ester propanoic acid0FormulationI0.025 mg/ml 3-methyl-1-butanol0Formulation I0.815 mg/ml 3-methyl-butyl acetate2Formulation I0.144 mg/ml 2-meth-yl-butyl acetate0Formulation I0.587 mg/ml benzaldehyde0Formulation I0.043 mg/ml isoamyl isovalerate13FormulationI0.785 mg/ml 3-methyl-butyl acetate + 0.562 mg/ml benzaldehyde11 When constituted with water, form G azithromycinin POS formulation II demonstrated approximately 71percent conversion to azithromycin dihydrate. POS formulation Iwhich is POS formulation II without the cherry, Trusil banana and vanilla flavorings, had no conversion to the azithro-mycin dihydrate when constituted with water. The constitution of POS formulation I with 3-methyl-butyl acetate and




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isoamyl isovalerate solutions, instead of water, exhibited an increased conversion to azithromycin dihydrate. As a resultof this observation it is evident that an azithromycin POS formulation will be more stable if the levels of these organiccomponents are minimized, or absent from the constituted POS all together. Flavorings should be chosen which donot contain these organic components for optimal POS stability. Furthermore, the stability of a constituted POS for-mulation can be improved by substituting flavorings that contain small amounts of these organic components for thosein the formulation that have large amounts of these organic components. It was also demonstrated that these organiccomponents may not enhance the conversion in an independent manner. Combinations of organic components, asdemonstrated through constitution with a 0.785 mg/ml 3-methyl-butyl acetate and 0.562 mg/ml benzaldehyde solution,may also interact to further facilitate the formation of the dihydrate species as compared to the effect of individualisolated components. For this reason it is beneficial not only to avoid such combinations of components through carefulflavoring choices, but also to choose flavorings with the least amount of organic components in order to minimize theprobability of observing such a phenomenon.

With iso-pentyl acetate, water, benzaldehyde, Time= 24h, T= 20 °C , Conversion of starting material


2 % Example Name 3The data showed that both the sucrose and vanilla flavorings contain only trace amounts of volatile organics that couldresult in the azithromycin form conversion. This correlated well to the lower conversion rate of these two formulationcomponents. The Trusil cherry and banana flavorings, however, appeared to have significant amounts of volatile or-ganics that may be responsible for the greater conversion enhancing behavior of these excipients. Standards of theseidentified solvent components were then used to investigate the source of the stability problem introduced by theseflavorings. The estimated concentration of each solvent in a constituted POS was calculated based on the GC-MSquantification of the specified solvent in the flavorings. Aqueous solutions of each solvent/component were then createdat these concentrations and 18 mls of each solvent-solution was used to constitute an unflavored POS formulation Isample using form G. The constituted drug suspensions were stored at room temperature for 24-hours, before beingfiltered and analyzed by SS-NMR for quantification of azithromycin form change over this interval. POS formulations Iand II were constituted with 18 mls of water and stored identically to serve as controls for this experiment. The resultsof this investigation can be seen in Table 8, below. [Table 8.] Effects of Flavoring Components Upon Azithromycin FormG Conversion Form G POS FormulationConstitution Medium (18 mL)percentForm AFormulation IIWater71FormulationIWater0Formulation I0.197 mg/ml ethyl acetate0Formulation I0.002 mg/ml ethyl ester propanoic acid0FormulationI0.025 mg/ml 3-methyl-1-butanol0Formulation I0.815 mg/ml 3-methyl-butyl acetate2Formulation I0.144 mg/ml 2-meth-yl-butyl acetate0Formulation I0.587 mg/ml benzaldehyde0Formulation I0.043 mg/ml isoamyl isovalerate13FormulationI0.785 mg/ml 3-methyl-butyl acetate + 0.562 mg/ml benzaldehyde11 When constituted with water, form G azithromycinin POS formulation II demonstrated approximately 71percent conversion to azithromycin dihydrate. POS formulation Iwhich is POS formulation II without the cherry, Trusil banana and vanilla flavorings, had no conversion to the azithro-mycin dihydrate when constituted with water. The constitution of POS formulation I with 3-methyl-butyl acetate andisoamyl isovalerate solutions, instead of water, exhibited an increased conversion to azithromycin dihydrate. As a resultof this observation it is evident that an azithromycin POS formulation will be more stable if the levels of these organiccomponents are minimized, or absent from the constituted POS all together. Flavorings should be chosen which donot contain these organic components for optimal POS stability. Furthermore, the stability of a constituted POS for-mulation can be improved by substituting flavorings that contain small amounts of these organic components for thosein the formulation that have large amounts of these organic components. It was also demonstrated that these organiccomponents may not enhance the conversion in an independent manner. Combinations of organic components, asdemonstrated through constitution with a 0.785 mg/ml 3-methyl-butyl acetate and 0.562 mg/ml benzaldehyde solution,may also interact to further facilitate the formation of the dihydrate species as compared to the effect of individualisolated components. For this reason it is beneficial not only to avoid such combinations of components through carefulflavoring choices, but also to choose flavorings with the least amount of organic components in order to minimize theprobability of observing such a phenomenon.

With iso-pentyl acetate, water, Time= 24h, T= 20 °C , Conversion of starting material


2 - 6 % Example Name 2To evaluate a proposed excipient, the active dose of the azithromycin was suspended with the desired amount ofpotential excipient in a 0.1 M phosphate buffer system adjusted to a pH of 8.16. The buffer system was created bydissolving 13.738 g of NaH2PO4*H2O in 900 ml of water, adjusting the pH to 8.16 with sodium hydroxide, and dilutingthe solution to 1 liter with water. The sample, once constituted with buffer, was then stored at room temperature for thedesired constituted product shelf-life. The azithromycin product was then isolated through filtration, and the resulting




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solid filtrate analyzed by a Solid-State Nuclear Magnetic Resonance method described previously that allows for quan-titation of the dihydrate form present. The effect of various individual flavoring components and of sucrose upon con-version of azithromycin form G to azithromycin dihydrate (form A), in suspensions, were evaluated as follows. An 820mg dose of form G azithromycin was weighed and mixed with 200 mg of each flavoring or sucrose. The mass of eachflavoring, used in this test, was chosen to match that of the anticipated required amount for effective flavoring in theconstituted POS. In this example, five flavorings, specifically artificial creme de vanilla, BC banana, Trusil banana, Trusilcherry and artificial grape were investigated in addition to sucrose. Each of the binary samples were then constitutedwith 18 mls of pH=8.16 buffer and stored for 1, 5 and 10-days at room temperature. A control suspension of azithromycinform G constituted with 18 mls of pH=8.16 buffer was run with each series of experiments using the same storageconditions. Upon completion of the constituted storage time period these samples were filtered to isolate drug productand analyzed using the SS-NMR method to quantify the amount of azithromycin dihydrate present. The results of thesestudies are provided in the following Table 3. [Table 3.] Effect of Flavorings and Sucrose On Conversion of AzithromycinForm G to Form A) FormulationsConstituted 1 day (Δ percentForm A)Constituted 5 days (Δ percentForm A)Constituted10 days (Δ percentForm A)Artificial Creme de Vanilla Flavor0percent4percent30percentBC Banana Flavor0per-cent27percentACTrusil Banana Flavor32percent57percentACSucrose2percent1percent6percentTrusil Cherry Fla-vor32percent75percentACArtificial Grape Flavor57percent75percentAC AC means all converted to form A As shownpreviously in Example 1, azithromycin form G, in combination with only water, experienced significant conversion toform A over the 10-day constitution interval. Further, when combined with a flavoring, such as Artificial Creme de vanilla,artificial grape, Trusil cherry, BC banana or Trusil banana, the rate of conversion substantially increased. Thus, thistest shows that these five flavorings need to be stabilized for use in oral suspension formulations of azithromycin formG with a 5-10 day constituted shelf-life. However, suspensions with Artificial Creme de vanilla and BC banana flavoringsdid not exhibit conversion to azithromycin dihydrate (form A) during the first day after constitution. Further, the presenceof sucrose, without flavoring, appears to have stabilized the azithromycin form G in a constituted suspension such thatonly minimal conversion to form A was observed over the 10-day period. This example demonstrated a simple methodfor choosing suitable excipients for non-dihydrate azithromycin oral suspensions that will minimize form conversion.

With water, sugar powder, Time= 24 - 240h, T= 20 °C , pH= 8.16, Aqueous phosphate buffer, Conversion of startingmaterial


0 - 30 % Example Name 2To evaluate a proposed excipient, the active dose of the azithromycin was suspended with the desired amount ofpotential excipient in a 0.1 M phosphate buffer system adjusted to a pH of 8.16. The buffer system was created bydissolving 13.738 g of NaH2PO4*H2O in 900 ml of water, adjusting the pH to 8.16 with sodium hydroxide, and dilutingthe solution to 1 liter with water. The sample, once constituted with buffer, was then stored at room temperature for thedesired constituted product shelf-life. The azithromycin product was then isolated through filtration, and the resultingsolid filtrate analyzed by a Solid-State Nuclear Magnetic Resonance method described previously that allows for quan-titation of the dihydrate form present. The effect of various individual flavoring components and of sucrose upon con-version of azithromycin form G to azithromycin dihydrate (form A), in suspensions, were evaluated as follows. An 820mg dose of form G azithromycin was weighed and mixed with 200 mg of each flavoring or sucrose. The mass of eachflavoring, used in this test, was chosen to match that of the anticipated required amount for effective flavoring in theconstituted POS. In this example, five flavorings, specifically artificial creme de vanilla, BC banana, Trusil banana, Trusilcherry and artificial grape were investigated in addition to sucrose. Each of the binary samples were then constitutedwith 18 mls of pH=8.16 buffer and stored for 1, 5 and 10-days at room temperature. A control suspension of azithromycinform G constituted with 18 mls of pH=8.16 buffer was run with each series of experiments using the same storageconditions. Upon completion of the constituted storage time period these samples were filtered to isolate drug productand analyzed using the SS-NMR method to quantify the amount of azithromycin dihydrate present. The results of thesestudies are provided in the following Table 3. [Table 3.] Effect of Flavorings and Sucrose On Conversion of AzithromycinForm G to Form A) FormulationsConstituted 1 day (Δ percentForm A)Constituted 5 days (Δ percentForm A)Constituted10 days (Δ percentForm A)Artificial Creme de Vanilla Flavor0percent4percent30percentBC Banana Flavor0per-cent27percentACTrusil Banana Flavor32percent57percentACSucrose2percent1percent6percentTrusil Cherry Fla-vor32percent75percentACArtificial Grape Flavor57percent75percentAC AC means all converted to form A As shownpreviously in Example 1, azithromycin form G, in combination with only water, experienced significant conversion toform A over the 10-day constitution interval. Further, when combined with a flavoring, such as Artificial Creme de vanilla,artificial grape, Trusil cherry, BC banana or Trusil banana, the rate of conversion substantially increased. Thus, thistest shows that these five flavorings need to be stabilized for use in oral suspension formulations of azithromycin formG with a 5-10 day constituted shelf-life. However, suspensions with Artificial Creme de vanilla and BC banana flavoringsdid not exhibit conversion to azithromycin dihydrate (form A) during the first day after constitution. Further, the presenceof sucrose, without flavoring, appears to have stabilized the azithromycin form G in a constituted suspension such that



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only minimal conversion to form A was observed over the 10-day period. This example demonstrated a simple methodfor choosing suitable excipients for non-dihydrate azithromycin oral suspensions that will minimize form conversion.

With Artifical Creme de Vanilla Flavour, water, Time= 24 - 240h, T= 20 °C , pH= 8.16, Aqueous phosphate buffer,Conversion of starting material



With BC Banana Flavour, water, Time= 24 - 240h, T= 20 °C , pH= 8.16, Aqueous phosphate buffer, Conversion ofstarting material


O

OH

O O

OH O

O

O

N

N

O

HO

OH

OH

O H H

2

OH

HO

O OH

O H

OH

OH

O

OH

O O

HO

O

O

HO

O

O

O

N

N

O

HO

OH

HO

H 2 O

2


93 % Example Name 5





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Examples 2 to 6: Preparation of azithromycin L-malate monohydrate from L-malic acidThe procedure of Example 1was repeated except that azithromycin, L-malic acid and the solvent as shown in Table 3 were used, to obtain the titlecompound. Table 3

in acetone, T= 0 - 20 °C , Product distribution / selectivity



in ethanol, T= 0 - 20 °C , Product distribution / selectivity


53 - 90 % Example Name 1; 4Example 1: Preparation of azithromycin L-malate monohvdrate from L-malic acid 100.Og of azithromycin dihydrate(127mmol) was dissolved in 1,000 ml of 95percent 2-propanol, and 34.1g of L-malic acid (254mmol) having an opticalpurity of 99.7percent ee was added thereto, followed by stirring the resulting solution overnight at room temperatureand then for 2 hours at 0 to 5 C . The precipitate formed was filtered, washed with cold 2-propanol, and dried at 45 C,to obtain 118.3 g of the title compound (yield: 90percent) as a white crystal.Examples 2 to 6: Preparation of azithromycinL-malate monohydrate from L-malic acidThe procedure of Example 1 was repeated except that azithromycin, L-malicacid and the solvent as shown in Table 3 were used, to obtain the title compound. Table 3

in isopropyl alcohol, T= 0 - 20 °C , Product distribution / selectivity


HO

HO

O OH O

OH

O O

OH

O

O

HO

O

O O

N N

O

HO

OH

OH HO

OH O

HO

O

OH O

O OH

O

O

HO

O

O

O

N

N

O

HO

OH

HO H

H

2 3


Example Name 4Example Title Example 4. Preparation of azithromycin citrate20g of azithromycin dihydrate and 3.5g of citric acid monohydrate are dissolved at ambient temperature in 50 ml ofethanol, filtered and the solvent is evaporated at low pressure. 24.9g of a white solid is obtained, containing up to 2.0percent of ethanol and up to 7percent of water. The X-ray diffraction spectrum confirms that it is an amorphous product(Fig. 10). Figures 10,11 and 12 show the X-ray diffraction spectrum, the carbon 13 nuclear magnetic resonance spec-trum (13C-NMR) in solid state and the IR spectrum, recorded on KBr tablet, respectively.

in ethanol, T= 20 °C


Example Name 5Example Title Example 5. Preparation of azithromycin citrate20g of azithromycin dihydrate and 3. 5g of citric acid are added to 50 ml of water. The mixture is stirred at ambienttemperature and the insoluble material filtered. The solution is concentrated at low pressure to a KF of around 5percent,yielding 23. LG of azithromycin citrate. Figures XIII, XIV and XV show the X-ray diffraction spectrum, the carbon 13







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nuclear magnetic resonance spectrum (13C-NMR) in solid state and the IR spectrum, recorded on KBr tablet, respec-tively.Example 6. Preparation of azithromycin citrate solutions Azithromycin citrate solutions are prepared by adding20g of azithromycin, 3.5g of citric acid and the corresponding amount of water (35 to 94g of water), stirring at ambienttemperature for a time ranging between 30 and 60 minutes, and finally filtering to remove insoluble material. The solutionis stable at ambient temperature.

in water, T= 20 °C


O

O OH

O

O

OH

O O

O

N H

N

O OH

OH

HO

O OH

O

O OH

O O

O

N

N

O OH

OH

HO


86.9 % With formic acid in chloroform, water, Time= 10h, Heating

Djokic, Slobodan; Kobrehel, Gabrijela; Lopotar, Nevenka; Kamenar, Boris; Nagl, Ante; Mrvos, Draginja; Journalof Chemical Research, Miniprint; nb. 5; (1988); p. 1239 - 1261View in Reaxys

O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH

HO

OH O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH

H

H

H 2 O


Example Name 2.AExample Title Example 2; Preparation of the Orthorhombic Pseudopolymorph of Formula Ib (S = tert-butanol); (MethodA)Crude [9-DEOXO-9A-AZA-9A-METHYL-9A-HOMOERYTHROMYCIN] A (10.0 g, having a water conternt of 5.7per-cent) was dissolved in 20 ml tert-butanol at a temperature of [60.deg.C.] The solution was treated with actived carbon,filtered, and cooled to room temperature over a period of 2 hours. The precipitated crystals were allowed to stand atroom temperature for a further 15 hours. The crystals were isolated and dried at atmospheric pressure and roomtemperature to constant weight. The product was lO. Og of a crystalline orthorhombic isostructural pseudopolymorphof Formula Ib (S = tert-butanol). The water content was 2.17percent, and the [TERT-] butanol content was 8.6percent.Upon single x-ray diffraction analysis, the orthorhombic pseudopolymorph was characterized as identified in Table 1Figure 3.









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O

OH

O O

OH O

O

O

N

N

O

HO

OH

OH

O H H

OH

HO

O OH

O H

OH

OH

O

OH

O O

HO

O

O

HO

O

O

O

N

N

O

HO

OH

HO

H 2 O

2





OH

OH

O

HO

O

O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH

OH

OH

O

OH

O O

HO

O

O

HO

O

O

O

N

N

O

HO

OH

HO 2


Example Name 8Example Title Preparation of Azithromycin L-Malate Monohydrate from DL-Malic Acid100.0 g of azithromycin dihydrate (127 mmol) was dissolved in 1,000 ml of 95percent 2-propanol, and 34.1 g of DL-malic acid (254 mmol, an optical purity of 1.7percent ee in favor of L-malic acid) was added thereto, followed by stirringthe resulting solution overnight at room temperature, and then, for 2 hours at 0 to 5.deg. C. The precipitate formed wasfiltered, washed with cold 2-propanol, and dried at 45.deg. C., to obtain 61.8 g of white crystalline powders (yield:47percent).M.P.: 170174.deg. C.Specific rotation, [α]D 20: -33.7.deg. (c=1, methanol)Moisture content (Karl-Fisher ti-trator): 1.85percentOptical purity of malic acid after salt formation (HPLC): 80.0percent ee in favor of L-malic acid56.0g of the crystalline powders obtained above was recrystallized from 95percent 2-propanol, to obtain 45.2 g of the titlecompound (yield: 80percent).M.P.: 172175.deg. C.Specific rotation, [α]D 20: -33.0.deg. (c=1, methanol)Moisture content(Karl-Fisher titrator): 1.81percentOptical purity of malic acid (HPLC): 98.9percent ee of L-malic acidXPRD and IR ab-sorption spectra of the compound thus obtained were the same as those of Example 1.

in water, isopropyl alcohol, T= 0 - 20 °C







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HO

O

O

N

O

O

HO O

O

O

O

HO

OH

N

O HO

O

O

HO

O

O

O

N N

O

HO

OH

HO


Reaction Steps: 21: 66 percent / H2 / PtO2 / acetic acid / 2 h / 51714.8 Torr2: 98 percent / H2O; CHCl3 / 1.5 h / 70 °CWith hydrogen, platinum(IV) oxide in chloroform, water, acetic acid

Wilkening, Robert R.; Ratcliffe, Ronald W.; Doss, George A.; Mosley, Ralph T.; Ball, Richard G.; Tetrahedron;vol. 53; nb. 50; (1997); p. 16923 - 16944View in Reaxys

OH O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH

H

H

H 2 O

O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH


Example Name 14Example Title Example 14; Preparation of Stable Amorphous [9-DEOXO-9A-AZA-9A-METHYL-9A-HOMOERYTHRO-MYCIN A,] from the Pseudopolymorph Ib (S=tert-butanol)The orthorhombic pseudopolymorph of Formula Ib (S = tert-butanol) obtained according to Example 2, was dried at[80.deg.C] under a reduced pressure of 13 Pa to constant weight. The yield and purity of the stable amorphous 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A thus obtained were identical to those in Example 11

, T= 80 °C , p= 0.0975098Torr


Example Name 16Example Title Example 16; Preparation of Stable Amorphous 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, fromthe Pseudopolymorph Ib (S=tert-butanol)The orthorhombic pseudopolymorph of Formula Ib (S = tert-butanol), obtained according to Example 2, was sublimedat a temperature of [95.deg.C] under a reduced pressure of 1 Pa to constant weight. The yield and purity of the stableamorphous 9-deoxo-9a-aza-9a-methyl-9a- homoerythromycin A thus obtained were identical to those of Example 11

, T= 95 °C , p= 0.00750075Torr








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OH

O OH

O

O

HO

O

O

O

N

N

O

HO

OH

OH

O H

H

0.5

O

OH

O O

OH O

O

O

N

N

O

HO

OH

OH

O H H

2


6 % Example Name 3An identical test was also performed using form F azithromycin. The calculated solvent levels were again used to createsolutions of these single components in water and used to constitute samples of POS formulation I using form F. Theconstituted drug suspensions were stored at room temperature for 24-hours, before being filtered and analyzed by SS-NMR for quantification of azithromycin form change over this interval. POS formulation II was constituted with waterand stored identically to serve as a control for this experiment. The design and results of this investigation can be seenin Table 9. [Table 9.] Effects of Flavoring Components Upon Azithromycin Form F Conversion Form F POS Formula-tionConstitution Medium (18 mL)SS-NMR Evaluation after 24 hrs constitutionpercentFpercentApercentG FormulationIIWater05941Formulation I0.922 mg/ml 3-methyl-butyl acetate000Formulation I0.0577 mg/ml benzaldehyde000For-mulation I1.666 mg/ml 3-methyl-butyl acetate050Formulation I0.922 mg/ml 3-methyl-butyl acetate + 0.0577 mg/mlbenzaldehyde060 Form F also demonstrated form conversion in the presence of organic flavoring components includ-ing 3-methyl-butyl acetate, either separately or in combination with benzaldehyde. It was also observed during thisexperiment that form F azithromycin had a tendency to convert to form G or other forms.

With iso-pentyl acetate, water, benzaldehyde, Time= 24h, T= 20 °C , Reactivity (does not react)


Example Name 3An identical test was also performed using form F azithromycin. The calculated solvent levels were again used to createsolutions of these single components in water and used to constitute samples of POS formulation I using form F. Theconstituted drug suspensions were stored at room temperature for 24-hours, before being filtered and analyzed by SS-NMR for quantification of azithromycin form change over this interval. POS formulation II was constituted with waterand stored identically to serve as a control for this experiment. The design and results of this investigation can be seenin Table 9. [Table 9.] Effects of Flavoring Components Upon Azithromycin Form F Conversion Form F POS Formula-tionConstitution Medium (18 mL)SS-NMR Evaluation after 24 hrs constitutionpercentFpercentApercentG FormulationIIWater05941Formulation I0.922 mg/ml 3-methyl-butyl acetate000Formulation I0.0577 mg/ml benzaldehyde000For-mulation I1.666 mg/ml 3-methyl-butyl acetate050Formulation I0.922 mg/ml 3-methyl-butyl acetate + 0.0577 mg/mlbenzaldehyde060 Form F also demonstrated form conversion in the presence of organic flavoring components includ-ing 3-methyl-butyl acetate, either separately or in combination with benzaldehyde. It was also observed during thisexperiment that form F azithromycin had a tendency to convert to form G or other forms.

With iso-pentyl acetate, water, Time= 24h, T= 20 °C , Reactivity (does not react)


Example Name 4This example demonstrates that when excipients, which can decrease surface tension, such as anionic and non-ionicsurfactants and surface active polymers, are incorporated into a POS formulation, the non-dihydrate azithromycin insuspension was stabilized against conversion. Forms F and M azithromycin were formulated into POS formulation II.A series of surfactants and polymers were then added to these formulations and the resulting samples constituted with18mls of water. After 24-hours of room temperature storage the samples were filtered and analyzed by SS-NMR forquantitation of dihydrate species present. The data are presented in Tables 10 and 11 and are given as the percentthat is converted to form A relative to a control sample. Thus, additives with conversion values greater than 100percentshow that more non-dihydrate azithromycin was converted to form A than in the control sample while values less than





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100percent show that the additive is decreasing the conversion to form A compared to the control sample. The controlsample consisted of non-dihydrate azithromycin form F or form M in formulation II, which was shown to promote con-version to azithromycin dihydrate (form A). The control sample was constituted with water, stored and analyzed iden-tically to the additive samples as described above. [Table 10.] Addition of Polymeric and Surfactant Components toSlow Form F Conversion AdditiveAdditive Level (percentw/v)Surface Tension (dyne/cm)percent Conversion to FormA Relative to the Control SampleSodium Dioctyl Sulfosuccinate125.61 0Sodium Lauryl Sulfate135.82 0HydroxypropylMethylcellulose Acetate Succinate143.73 23Hydroxypropyl Methylcellulose0.247.12 43Carboxymethylcellulose So-dium170.92 106Cellulose Acetate Phthalate1.551.33 136Polyvinylpyrrolidone168.32 1111Literature Value (Johnson,Barbara A., Kreuter, Jorg and Zografi, George, "Effects of Surfactants and Polymers on Advancing and RecedingContact Angles" Colloids and Surfaces, 17 (1986) 325-342.)2Surface tension of an aqueous solution of the polymer atthe concentration used in the suspension determined with a Kruss Tensiometer using the Wilhemy plate method atroom temperature.3Surface tension of the saturated aqueous solution of the polymer determined with a Kruss Tensi-ometer using the Wilhemy plate method at room temperature.[Table 11.] Addition of Polymeric and Surfactant Com-ponents to Slow Form M Conversion AdditiveAdditive Level (percentw/v)Surface Tension (dyne/cm)percent Conversionto Form A Relative to the Control SampleSodium Dioctyl Sulfosuccinate125.61 0Sodium Lauryl Sulfate135.82 0Igepal.(R). CO-6301323 8Pluronic.(R). F68NF143.21 10Hydroxypropyl Cellulose0.3421 72Hydroxypropyl Methylcellu-lose0.4471 97Polyvinylpyrrolidone168.32 1071Literature Value (Johnson, Barbara A., Kreuter, Jorg and Zografi,George, "Effects of Surfactants and Polymers on Advancing and Receding Contact Angles" Colloids and Surfaces, 17(1986) 325-342.)2Surface tension of an aqueous solution of the polymer at the concentration used in the suspensiondetermined with a Kruss Tensiometer using the Wilhemy plate method at room temperature.3GAF Chemicals Corp.,Technical Bulletin 2303-015R2 (1986) This example showed that additives which are surface active such as hydroxy-propyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate and sodium dioctyl sul-fosuccinate are effective in slowing the conversion of form F to the dihydrate form. The anionic surfactants, sodiumlauryl sulfate and sodium dioctyl sulfosuccinate, are also shown as effective for inhibiting conversion of a second non-dihydrate azithromycin form (form M). The cellulosic polymers, hydroxypropyl cellulose and hydroxypropyl methylcel-lulose, and the polyoxyethylene-polyoxypropylene copolymer Pluronic.(R). F68NF and the nonionic surfactant nonyl-phenoxy polyoxyethylene Igepal.(R). CO-630 were also found to slow the conversion of non-dihydrate azithromycinform M. The effectiveness of these additives is related to their surface activity as shown in Tables 10 and 11.

With water, polyvinylpyrrolidone, Time= 24h, T= 20 °C , Conversion of starting material


Example Name 4This example demonstrates that when excipients, which can decrease surface tension, such as anionic and non-ionicsurfactants and surface active polymers, are incorporated into a POS formulation, the non-dihydrate azithromycin insuspension was stabilized against conversion. Forms F and M azithromycin were formulated into POS formulation II.A series of surfactants and polymers were then added to these formulations and the resulting samples constituted with18mls of water. After 24-hours of room temperature storage the samples were filtered and analyzed by SS-NMR forquantitation of dihydrate species present. The data are presented in Tables 10 and 11 and are given as the percentthat is converted to form A relative to a control sample. Thus, additives with conversion values greater than 100percentshow that more non-dihydrate azithromycin was converted to form A than in the control sample while values less than100percent show that the additive is decreasing the conversion to form A compared to the control sample. The controlsample consisted of non-dihydrate azithromycin form F or form M in formulation II, which was shown to promote con-version to azithromycin dihydrate (form A). The control sample was constituted with water, stored and analyzed iden-tically to the additive samples as described above. [Table 10.] Addition of Polymeric and Surfactant Components toSlow Form F Conversion AdditiveAdditive Level (percentw/v)Surface Tension (dyne/cm)percent Conversion to FormA Relative to the Control SampleSodium Dioctyl Sulfosuccinate125.61 0Sodium Lauryl Sulfate135.82 0HydroxypropylMethylcellulose Acetate Succinate143.73 23Hydroxypropyl Methylcellulose0.247.12 43Carboxymethylcellulose So-dium170.92 106Cellulose Acetate Phthalate1.551.33 136Polyvinylpyrrolidone168.32 1111Literature Value (Johnson,Barbara A., Kreuter, Jorg and Zografi, George, "Effects of Surfactants and Polymers on Advancing and RecedingContact Angles" Colloids and Surfaces, 17 (1986) 325-342.)2Surface tension of an aqueous solution of the polymer atthe concentration used in the suspension determined with a Kruss Tensiometer using the Wilhemy plate method atroom temperature.3Surface tension of the saturated aqueous solution of the polymer determined with a Kruss Tensi-ometer using the Wilhemy plate method at room temperature.[Table 11.] Addition of Polymeric and Surfactant Com-ponents to Slow Form M Conversion AdditiveAdditive Level (percentw/v)Surface Tension (dyne/cm)percent Conversionto Form A Relative to the Control SampleSodium Dioctyl Sulfosuccinate125.61 0Sodium Lauryl Sulfate135.82 0Igepal.(R). CO-6301323 8Pluronic.(R). F68NF143.21 10Hydroxypropyl Cellulose0.3421 72Hydroxypropyl Methylcellu-lose0.4471 97Polyvinylpyrrolidone168.32 1071Literature Value (Johnson, Barbara A., Kreuter, Jorg and Zografi,George, "Effects of Surfactants and Polymers on Advancing and Receding Contact Angles" Colloids and Surfaces, 17(1986) 325-342.)2Surface tension of an aqueous solution of the polymer at the concentration used in the suspension



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determined with a Kruss Tensiometer using the Wilhemy plate method at room temperature.3GAF Chemicals Corp.,Technical Bulletin 2303-015R2 (1986) This example showed that additives which are surface active such as hydroxy-propyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate and sodium dioctyl sul-fosuccinate are effective in slowing the conversion of form F to the dihydrate form. The anionic surfactants, sodiumlauryl sulfate and sodium dioctyl sulfosuccinate, are also shown as effective for inhibiting conversion of a second non-dihydrate azithromycin form (form M). The cellulosic polymers, hydroxypropyl cellulose and hydroxypropyl methylcel-lulose, and the polyoxyethylene-polyoxypropylene copolymer Pluronic.(R). F68NF and the nonionic surfactant nonyl-phenoxy polyoxyethylene Igepal.(R). CO-630 were also found to slow the conversion of non-dihydrate azithromycinform M. The effectiveness of these additives is related to their surface activity as shown in Tables 10 and 11.

With water, cellulose acetate phthalate, Time= 24h, T= 20 °C , Conversion of starting material


Example Name 4This example demonstrates that when excipients, which can decrease surface tension, such as anionic and non-ionicsurfactants and surface active polymers, are incorporated into a POS formulation, the non-dihydrate azithromycin insuspension was stabilized against conversion. Forms F and M azithromycin were formulated into POS formulation II.A series of surfactants and polymers were then added to these formulations and the resulting samples constituted with18mls of water. After 24-hours of room temperature storage the samples were filtered and analyzed by SS-NMR forquantitation of dihydrate species present. The data are presented in Tables 10 and 11 and are given as the percentthat is converted to form A relative to a control sample. Thus, additives with conversion values greater than 100percentshow that more non-dihydrate azithromycin was converted to form A than in the control sample while values less than100percent show that the additive is decreasing the conversion to form A compared to the control sample. The controlsample consisted of non-dihydrate azithromycin form F or form M in formulation II, which was shown to promote con-version to azithromycin dihydrate (form A). The control sample was constituted with water, stored and analyzed iden-tically to the additive samples as described above. [Table 10.] Addition of Polymeric and Surfactant Components toSlow Form F Conversion AdditiveAdditive Level (percentw/v)Surface Tension (dyne/cm)percent Conversion to FormA Relative to the Control SampleSodium Dioctyl Sulfosuccinate125.61 0Sodium Lauryl Sulfate135.82 0HydroxypropylMethylcellulose Acetate Succinate143.73 23Hydroxypropyl Methylcellulose0.247.12 43Carboxymethylcellulose So-dium170.92 106Cellulose Acetate Phthalate1.551.33 136Polyvinylpyrrolidone168.32 1111Literature Value (Johnson,Barbara A., Kreuter, Jorg and Zografi, George, "Effects of Surfactants and Polymers on Advancing and RecedingContact Angles" Colloids and Surfaces, 17 (1986) 325-342.)2Surface tension of an aqueous solution of the polymer atthe concentration used in the suspension determined with a Kruss Tensiometer using the Wilhemy plate method atroom temperature.3Surface tension of the saturated aqueous solution of the polymer determined with a Kruss Tensi-ometer using the Wilhemy plate method at room temperature.[Table 11.] Addition of Polymeric and Surfactant Com-ponents to Slow Form M Conversion AdditiveAdditive Level (percentw/v)Surface Tension (dyne/cm)percent Conversionto Form A Relative to the Control SampleSodium Dioctyl Sulfosuccinate125.61 0Sodium Lauryl Sulfate135.82 0Igepal.(R). CO-6301323 8Pluronic.(R). F68NF143.21 10Hydroxypropyl Cellulose0.3421 72Hydroxypropyl Methylcellu-lose0.4471 97Polyvinylpyrrolidone168.32 1071Literature Value (Johnson, Barbara A., Kreuter, Jorg and Zografi,George, "Effects of Surfactants and Polymers on Advancing and Receding Contact Angles" Colloids and Surfaces, 17(1986) 325-342.)2Surface tension of an aqueous solution of the polymer at the concentration used in the suspensiondetermined with a Kruss Tensiometer using the Wilhemy plate method at room temperature.3GAF Chemicals Corp.,Technical Bulletin 2303-015R2 (1986) This example showed that additives which are surface active such as hydroxy-propyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate and sodium dioctyl sul-fosuccinate are effective in slowing the conversion of form F to the dihydrate form. The anionic surfactants, sodiumlauryl sulfate and sodium dioctyl sulfosuccinate, are also shown as effective for inhibiting conversion of a second non-dihydrate azithromycin form (form M). The cellulosic polymers, hydroxypropyl cellulose and hydroxypropyl methylcel-lulose, and the polyoxyethylene-polyoxypropylene copolymer Pluronic.(R). F68NF and the nonionic surfactant nonyl-phenoxy polyoxyethylene Igepal.(R). CO-630 were also found to slow the conversion of non-dihydrate azithromycinform M. The effectiveness of these additives is related to their surface activity as shown in Tables 10 and 11.

With water, hydroxypropyl methylcellulose, Time= 24h, T= 20 °C , Conversion of starting material


Example Name 4This example demonstrates that when excipients, which can decrease surface tension, such as anionic and non-ionicsurfactants and surface active polymers, are incorporated into a POS formulation, the non-dihydrate azithromycin insuspension was stabilized against conversion. Forms F and M azithromycin were formulated into POS formulation II.A series of surfactants and polymers were then added to these formulations and the resulting samples constituted with




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18mls of water. After 24-hours of room temperature storage the samples were filtered and analyzed by SS-NMR forquantitation of dihydrate species present. The data are presented in Tables 10 and 11 and are given as the percentthat is converted to form A relative to a control sample. Thus, additives with conversion values greater than 100percentshow that more non-dihydrate azithromycin was converted to form A than in the control sample while values less than100percent show that the additive is decreasing the conversion to form A compared to the control sample. The controlsample consisted of non-dihydrate azithromycin form F or form M in formulation II, which was shown to promote con-version to azithromycin dihydrate (form A). The control sample was constituted with water, stored and analyzed iden-tically to the additive samples as described above. [Table 10.] Addition of Polymeric and Surfactant Components toSlow Form F Conversion AdditiveAdditive Level (percentw/v)Surface Tension (dyne/cm)percent Conversion to FormA Relative to the Control SampleSodium Dioctyl Sulfosuccinate125.61 0Sodium Lauryl Sulfate135.82 0HydroxypropylMethylcellulose Acetate Succinate143.73 23Hydroxypropyl Methylcellulose0.247.12 43Carboxymethylcellulose So-dium170.92 106Cellulose Acetate Phthalate1.551.33 136Polyvinylpyrrolidone168.32 1111Literature Value (Johnson,Barbara A., Kreuter, Jorg and Zografi, George, "Effects of Surfactants and Polymers on Advancing and RecedingContact Angles" Colloids and Surfaces, 17 (1986) 325-342.)2Surface tension of an aqueous solution of the polymer atthe concentration used in the suspension determined with a Kruss Tensiometer using the Wilhemy plate method atroom temperature.3Surface tension of the saturated aqueous solution of the polymer determined with a Kruss Tensi-ometer using the Wilhemy plate method at room temperature.[Table 11.] Addition of Polymeric and Surfactant Com-ponents to Slow Form M Conversion AdditiveAdditive Level (percentw/v)Surface Tension (dyne/cm)percent Conversionto Form A Relative to the Control SampleSodium Dioctyl Sulfosuccinate125.61 0Sodium Lauryl Sulfate135.82 0Igepal.(R). CO-6301323 8Pluronic.(R). F68NF143.21 10Hydroxypropyl Cellulose0.3421 72Hydroxypropyl Methylcellu-lose0.4471 97Polyvinylpyrrolidone168.32 1071Literature Value (Johnson, Barbara A., Kreuter, Jorg and Zografi,George, "Effects of Surfactants and Polymers on Advancing and Receding Contact Angles" Colloids and Surfaces, 17(1986) 325-342.)2Surface tension of an aqueous solution of the polymer at the concentration used in the suspensiondetermined with a Kruss Tensiometer using the Wilhemy plate method at room temperature.3GAF Chemicals Corp.,Technical Bulletin 2303-015R2 (1986) This example showed that additives which are surface active such as hydroxy-propyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate and sodium dioctyl sul-fosuccinate are effective in slowing the conversion of form F to the dihydrate form. The anionic surfactants, sodiumlauryl sulfate and sodium dioctyl sulfosuccinate, are also shown as effective for inhibiting conversion of a second non-dihydrate azithromycin form (form M). The cellulosic polymers, hydroxypropyl cellulose and hydroxypropyl methylcel-lulose, and the polyoxyethylene-polyoxypropylene copolymer Pluronic.(R). F68NF and the nonionic surfactant nonyl-phenoxy polyoxyethylene Igepal.(R). CO-630 were also found to slow the conversion of non-dihydrate azithromycinform M. The effectiveness of these additives is related to their surface activity as shown in Tables 10 and 11.

With water, carboxymethylcellulose sodium, Time= 24h, T= 20 °C , Conversion of starting material


Example Name 4This example demonstrates that when excipients, which can decrease surface tension, such as anionic and non-ionicsurfactants and surface active polymers, are incorporated into a POS formulation, the non-dihydrate azithromycin insuspension was stabilized against conversion. Forms F and M azithromycin were formulated into POS formulation II.A series of surfactants and polymers were then added to these formulations and the resulting samples constituted with18mls of water. After 24-hours of room temperature storage the samples were filtered and analyzed by SS-NMR forquantitation of dihydrate species present. The data are presented in Tables 10 and 11 and are given as the percentthat is converted to form A relative to a control sample. Thus, additives with conversion values greater than 100percentshow that more non-dihydrate azithromycin was converted to form A than in the control sample while values less than100percent show that the additive is decreasing the conversion to form A compared to the control sample. The controlsample consisted of non-dihydrate azithromycin form F or form M in formulation II, which was shown to promote con-version to azithromycin dihydrate (form A). The control sample was constituted with water, stored and analyzed iden-tically to the additive samples as described above. [Table 10.] Addition of Polymeric and Surfactant Components toSlow Form F Conversion AdditiveAdditive Level (percentw/v)Surface Tension (dyne/cm)percent Conversion to FormA Relative to the Control SampleSodium Dioctyl Sulfosuccinate125.61 0Sodium Lauryl Sulfate135.82 0HydroxypropylMethylcellulose Acetate Succinate143.73 23Hydroxypropyl Methylcellulose0.247.12 43Carboxymethylcellulose So-dium170.92 106Cellulose Acetate Phthalate1.551.33 136Polyvinylpyrrolidone168.32 1111Literature Value (Johnson,Barbara A., Kreuter, Jorg and Zografi, George, "Effects of Surfactants and Polymers on Advancing and RecedingContact Angles" Colloids and Surfaces, 17 (1986) 325-342.)2Surface tension of an aqueous solution of the polymer atthe concentration used in the suspension determined with a Kruss Tensiometer using the Wilhemy plate method atroom temperature.3Surface tension of the saturated aqueous solution of the polymer determined with a Kruss Tensi-ometer using the Wilhemy plate method at room temperature.[Table 11.] Addition of Polymeric and Surfactant Com-ponents to Slow Form M Conversion AdditiveAdditive Level (percentw/v)Surface Tension (dyne/cm)percent Conversionto Form A Relative to the Control SampleSodium Dioctyl Sulfosuccinate125.61 0Sodium Lauryl Sulfate135.82 0Igepal.



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(R). CO-6301323 8Pluronic.(R). F68NF143.21 10Hydroxypropyl Cellulose0.3421 72Hydroxypropyl Methylcellu-lose0.4471 97Polyvinylpyrrolidone168.32 1071Literature Value (Johnson, Barbara A., Kreuter, Jorg and Zografi,George, "Effects of Surfactants and Polymers on Advancing and Receding Contact Angles" Colloids and Surfaces, 17(1986) 325-342.)2Surface tension of an aqueous solution of the polymer at the concentration used in the suspensiondetermined with a Kruss Tensiometer using the Wilhemy plate method at room temperature.3GAF Chemicals Corp.,Technical Bulletin 2303-015R2 (1986) This example showed that additives which are surface active such as hydroxy-propyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate and sodium dioctyl sul-fosuccinate are effective in slowing the conversion of form F to the dihydrate form. The anionic surfactants, sodiumlauryl sulfate and sodium dioctyl sulfosuccinate, are also shown as effective for inhibiting conversion of a second non-dihydrate azithromycin form (form M). The cellulosic polymers, hydroxypropyl cellulose and hydroxypropyl methylcel-lulose, and the polyoxyethylene-polyoxypropylene copolymer Pluronic.(R). F68NF and the nonionic surfactant nonyl-phenoxy polyoxyethylene Igepal.(R). CO-630 were also found to slow the conversion of non-dihydrate azithromycinform M. The effectiveness of these additives is related to their surface activity as shown in Tables 10 and 11.

With hydroxypropyl methylcellulose acetate succinate, water, Time= 24h, T= 20 °C , Conversion of starting material


O OH O

H

O HO

O

O

HO

O

O

O

HN N

O

HO

OH

HO O HO

O

O

HO

O

O

O

N N

O

HO

OH

HO


98 % in chloroform, water, Time= 1.5h, T= 70 °C


O O

O

O

N HO

O

O

O

N

HO

O

HO

OH

Z

O HO

O

O

HO

O

O

O

N N

O

HO

OH

HO


Reaction Steps: 31: 21 percent / nitromethane / 2 h / 100 °C2: 66 percent / H2 / PtO2 / acetic acid / 2 h / 51714.8 Torr3: 98 percent / H2O; CHCl3 / 1.5 h / 70 °CWith hydrogen, platinum(IV) oxide in nitromethane, chloroform, water, acetic acid








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O

O O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH

H

H

H 2 O

O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH


Example Name 13Example Title Example 13; Preparation of Stable Amorphous 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, fromthe Pseudopolymorph la (S=1, 4-dioxane)The orthorhombic pseudopolymorph of Formula la (S = 1,4-dioxane) obtained according to Example 1, was dried at[50.deg.C] and a reduced pressure of 0.1 kPa to constant weight. The yield and purity of the stable amorphous [9-DEOXO-9A-AZA-9A-METHYL-9A-HOMOERYTHROMYCIN] A thus produced were identical to those of Example 11.

, T= 50 °C , p= 0.750075Torr


O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH

H

H

H 2 O

O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH


Example Name 15Example Title Example 15; Preparation of Stable Amorphous [9-DEOXO-9A-AZA-9A-METHYL-9A-HOMOERYTHRO-MYCIN A,] from the Pseudopolymorph Id (S=cyclohexane)The orthorhombic pseudopolymorph of Formula Id (S = cyclohexane) obtained according to Example 4, was dried at[80.deg.C] under a reduced pressure of 2 kPa to constant weight. The yield and purity of the stable amorphous 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A thus obtained were identical to those of Example 11

, T= 80 °C , p= 15.0015Torr







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O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH

O

OH

O O

OH O

O

O

N

N

O

HO

OH

OH

O H H


Example Name 3The crude azithromycin prepared in Example 1 (105 kg) was dissolved in about 304 L ethanol (95percent) at about70.deg. C. in a 800 L reaction vessel. The solution was then hot filtered through about 1 kg of Celite.(R)., and the filtratewas allowed to directly flow into about 304 kg of water in a 1,000-L reaction vessel. During the addition, the watertemperature was maintained at about 20.deg. C. The resulting slurry was stirred for about 5 hours. The precipitate wasfiltered and washed with water, providing about 109.4 kg of wet precipitate (contained 35.42percent water (w/w)). Thewet precipitate was slurried vigorously in about 700 L of water in a 1,000-L reaction vessel for about 5 hours at roomtemperature. The slurry was filtered, washed with water, and dried in stages to provide about 68.2 kg of crystallineazithromycin monohydrate. The water content, ethanol content, purity, stability, hygroscopicity, and other parametersare presented in Tables 1 and 2. Table 1 shows that the crystalline azithromycin monohydrate was stable and non-hygroscopic for 3 months when stored at 25.deg. C. and 60percent relative humidity. Table 2 shows that the crystallineazithromycin monohydrate was stable and non-hygroscopic for 3 months when stored at 40.deg. C. and 75percentrelative humidity.

With water in ethanol, Time= 10h, T= 20 - 70 °C , Industry scale, Purification / work up

Patent; Gutman, Daniella; Shahal, Leah; US2006/63725; (2006); (A1) EnglishView in Reaxys

O

OH

O O

OH O

O

O

N

N

O

HO

OH

OH

O H H

2

OH

OH

O

HO

O OH

OH

O

OH

O O

HO

O

O

HO

O

O

O

N

N

O

HO

OH

HO

H 2 O

2


47 % Example Name 8Example 8: Preparation of azithromycin L-malate monohvdrate from DL-malic acid100.0 g of azithromycin dihydrate(127mmol) was dissolved in 1,000 mi of 95percent 2-propanol, and 34.1g of DL-malic acid (254mmol5 an optical purityof 1.7percent ee in favor of L-malic acid) was added thereto, followed by stirring the resulting solution overnight at roomtemperature, and then, for 2 hours at 0 to 5 C . The precipitate formed was filtered, washed with cold 2-propanol, anddried at 45 C, to obtain 61.8 g of white crystalline powders (yield: 47percent).








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OH

OH

O

OH

O O

HO

O

O

HO

O

O

O

N

N

O

HO

OH

HO

H 2 O

2

OH

OH

O

OH

O O

HO

O

O

HO

O

O

O

N

N

O

HO

OH

HO 2


Example Name AReference Example 1 : Preparation of azithromycin L-malate anhydrateMethod A10.0g of azithromycin L-malate mon-ohydrate obtained in one of Examples 1 to 8 was dried under a reduced pressure (lmmHg) at 100 C for 10 hours, toobtain the title compound as white powders.


OH

O OH

O

O

HO

O

O

O

N

N

O

HO

OH

OH

O H

H

0.5

O

OH

O O

OH O

O

O

N

N

O

HO

OH

OH

O H H

2


Example Name 4This example demonstrates that when excipients, which can decrease surface tension, such as anionic and non-ionicsurfactants and surface active polymers, are incorporated into a POS formulation, the non-dihydrate azithromycin insuspension was stabilized against conversion. Forms F and M azithromycin were formulated into POS formulation II.A series of surfactants and polymers were then added to these formulations and the resulting samples constituted with18mls of water. After 24-hours of room temperature storage the samples were filtered and analyzed by SS-NMR forquantitation of dihydrate species present. The data are presented in Tables 10 and 11 and are given as the percentthat is converted to form A relative to a control sample. Thus, additives with conversion values greater than 100percentshow that more non-dihydrate azithromycin was converted to form A than in the control sample while values less than100percent show that the additive is decreasing the conversion to form A compared to the control sample. The controlsample consisted of non-dihydrate azithromycin form F or form M in formulation II, which was shown to promote con-version to azithromycin dihydrate (form A). The control sample was constituted with water, stored and analyzed iden-tically to the additive samples as described above. [Table 10.] Addition of Polymeric and Surfactant Components toSlow Form F Conversion AdditiveAdditive Level (percentw/v)Surface Tension (dyne/cm)percent Conversion to FormA Relative to the Control SampleSodium Dioctyl Sulfosuccinate125.61 0Sodium Lauryl Sulfate135.82 0HydroxypropylMethylcellulose Acetate Succinate143.73 23Hydroxypropyl Methylcellulose0.247.12 43Carboxymethylcellulose So-dium170.92 106Cellulose Acetate Phthalate1.551.33 136Polyvinylpyrrolidone168.32 1111Literature Value (Johnson,Barbara A., Kreuter, Jorg and Zografi, George, "Effects of Surfactants and Polymers on Advancing and RecedingContact Angles" Colloids and Surfaces, 17 (1986) 325-342.)2Surface tension of an aqueous solution of the polymer atthe concentration used in the suspension determined with a Kruss Tensiometer using the Wilhemy plate method atroom temperature.3Surface tension of the saturated aqueous solution of the polymer determined with a Kruss Tensi-ometer using the Wilhemy plate method at room temperature.[Table 11.] Addition of Polymeric and Surfactant Com-ponents to Slow Form M Conversion AdditiveAdditive Level (percentw/v)Surface Tension (dyne/cm)percent Conversionto Form A Relative to the Control SampleSodium Dioctyl Sulfosuccinate125.61 0Sodium Lauryl Sulfate135.82 0Igepal.(R). CO-6301323 8Pluronic.(R). F68NF143.21 10Hydroxypropyl Cellulose0.3421 72Hydroxypropyl Methylcellu-





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lose0.4471 97Polyvinylpyrrolidone168.32 1071Literature Value (Johnson, Barbara A., Kreuter, Jorg and Zografi,George, "Effects of Surfactants and Polymers on Advancing and Receding Contact Angles" Colloids and Surfaces, 17(1986) 325-342.)2Surface tension of an aqueous solution of the polymer at the concentration used in the suspensiondetermined with a Kruss Tensiometer using the Wilhemy plate method at room temperature.3GAF Chemicals Corp.,Technical Bulletin 2303-015R2 (1986) This example showed that additives which are surface active such as hydroxy-propyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate and sodium dioctyl sul-fosuccinate are effective in slowing the conversion of form F to the dihydrate form. The anionic surfactants, sodiumlauryl sulfate and sodium dioctyl sulfosuccinate, are also shown as effective for inhibiting conversion of a second non-dihydrate azithromycin form (form M). The cellulosic polymers, hydroxypropyl cellulose and hydroxypropyl methylcel-lulose, and the polyoxyethylene-polyoxypropylene copolymer Pluronic.(R). F68NF and the nonionic surfactant nonyl-phenoxy polyoxyethylene Igepal.(R). CO-630 were also found to slow the conversion of non-dihydrate azithromycinform M. The effectiveness of these additives is related to their surface activity as shown in Tables 10 and 11.

With Igepal.(R).CO-630, water, Time= 24h, T= 20 °C , Conversion of starting material



With water, polyvinylpyrrolidone, Time= 24h, T= 20 °C , Conversion of starting material


Example Name 4




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This example demonstrates that when excipients, which can decrease surface tension, such as anionic and non-ionicsurfactants and surface active polymers, are incorporated into a POS formulation, the non-dihydrate azithromycin insuspension was stabilized against conversion. Forms F and M azithromycin were formulated into POS formulation II.A series of surfactants and polymers were then added to these formulations and the resulting samples constituted with18mls of water. After 24-hours of room temperature storage the samples were filtered and analyzed by SS-NMR forquantitation of dihydrate species present. The data are presented in Tables 10 and 11 and are given as the percentthat is converted to form A relative to a control sample. Thus, additives with conversion values greater than 100percentshow that more non-dihydrate azithromycin was converted to form A than in the control sample while values less than100percent show that the additive is decreasing the conversion to form A compared to the control sample. The controlsample consisted of non-dihydrate azithromycin form F or form M in formulation II, which was shown to promote con-version to azithromycin dihydrate (form A). The control sample was constituted with water, stored and analyzed iden-tically to the additive samples as described above. [Table 10.] Addition of Polymeric and Surfactant Components toSlow Form F Conversion AdditiveAdditive Level (percentw/v)Surface Tension (dyne/cm)percent Conversion to FormA Relative to the Control SampleSodium Dioctyl Sulfosuccinate125.61 0Sodium Lauryl Sulfate135.82 0HydroxypropylMethylcellulose Acetate Succinate143.73 23Hydroxypropyl Methylcellulose0.247.12 43Carboxymethylcellulose So-dium170.92 106Cellulose Acetate Phthalate1.551.33 136Polyvinylpyrrolidone168.32 1111Literature Value (Johnson,Barbara A., Kreuter, Jorg and Zografi, George, "Effects of Surfactants and Polymers on Advancing and RecedingContact Angles" Colloids and Surfaces, 17 (1986) 325-342.)2Surface tension of an aqueous solution of the polymer atthe concentration used in the suspension determined with a Kruss Tensiometer using the Wilhemy plate method atroom temperature.3Surface tension of the saturated aqueous solution of the polymer determined with a Kruss Tensi-ometer using the Wilhemy plate method at room temperature.[Table 11.] Addition of Polymeric and Surfactant Com-ponents to Slow Form M Conversion AdditiveAdditive Level (percentw/v)Surface Tension (dyne/cm)percent Conversionto Form A Relative to the Control SampleSodium Dioctyl Sulfosuccinate125.61 0Sodium Lauryl Sulfate135.82 0Igepal.(R). CO-6301323 8Pluronic.(R). F68NF143.21 10Hydroxypropyl Cellulose0.3421 72Hydroxypropyl Methylcellu-lose0.4471 97Polyvinylpyrrolidone168.32 1071Literature Value (Johnson, Barbara A., Kreuter, Jorg and Zografi,George, "Effects of Surfactants and Polymers on Advancing and Receding Contact Angles" Colloids and Surfaces, 17(1986) 325-342.)2Surface tension of an aqueous solution of the polymer at the concentration used in the suspensiondetermined with a Kruss Tensiometer using the Wilhemy plate method at room temperature.3GAF Chemicals Corp.,Technical Bulletin 2303-015R2 (1986) This example showed that additives which are surface active such as hydroxy-propyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate and sodium dioctyl sul-fosuccinate are effective in slowing the conversion of form F to the dihydrate form. The anionic surfactants, sodiumlauryl sulfate and sodium dioctyl sulfosuccinate, are also shown as effective for inhibiting conversion of a second non-dihydrate azithromycin form (form M). The cellulosic polymers, hydroxypropyl cellulose and hydroxypropyl methylcel-lulose, and the polyoxyethylene-polyoxypropylene copolymer Pluronic.(R). F68NF and the nonionic surfactant nonyl-phenoxy polyoxyethylene Igepal.(R). CO-630 were also found to slow the conversion of non-dihydrate azithromycinform M. The effectiveness of these additives is related to their surface activity as shown in Tables 10 and 11.

With Pluronic.(R).F-68NF, water, Time= 24h, T= 20 °C , Conversion of starting material


Example Name 4This example demonstrates that when excipients, which can decrease surface tension, such as anionic and non-ionicsurfactants and surface active polymers, are incorporated into a POS formulation, the non-dihydrate azithromycin insuspension was stabilized against conversion. Forms F and M azithromycin were formulated into POS formulation II.A series of surfactants and polymers were then added to these formulations and the resulting samples constituted with18mls of water. After 24-hours of room temperature storage the samples were filtered and analyzed by SS-NMR forquantitation of dihydrate species present. The data are presented in Tables 10 and 11 and are given as the percentthat is converted to form A relative to a control sample. Thus, additives with conversion values greater than 100percentshow that more non-dihydrate azithromycin was converted to form A than in the control sample while values less than100percent show that the additive is decreasing the conversion to form A compared to the control sample. The controlsample consisted of non-dihydrate azithromycin form F or form M in formulation II, which was shown to promote con-version to azithromycin dihydrate (form A). The control sample was constituted with water, stored and analyzed iden-tically to the additive samples as described above. [Table 10.] Addition of Polymeric and Surfactant Components toSlow Form F Conversion AdditiveAdditive Level (percentw/v)Surface Tension (dyne/cm)percent Conversion to FormA Relative to the Control SampleSodium Dioctyl Sulfosuccinate125.61 0Sodium Lauryl Sulfate135.82 0HydroxypropylMethylcellulose Acetate Succinate143.73 23Hydroxypropyl Methylcellulose0.247.12 43Carboxymethylcellulose So-dium170.92 106Cellulose Acetate Phthalate1.551.33 136Polyvinylpyrrolidone168.32 1111Literature Value (Johnson,Barbara A., Kreuter, Jorg and Zografi, George, "Effects of Surfactants and Polymers on Advancing and RecedingContact Angles" Colloids and Surfaces, 17 (1986) 325-342.)2Surface tension of an aqueous solution of the polymer atthe concentration used in the suspension determined with a Kruss Tensiometer using the Wilhemy plate method at



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room temperature.3Surface tension of the saturated aqueous solution of the polymer determined with a Kruss Tensi-ometer using the Wilhemy plate method at room temperature.[Table 11.] Addition of Polymeric and Surfactant Com-ponents to Slow Form M Conversion AdditiveAdditive Level (percentw/v)Surface Tension (dyne/cm)percent Conversionto Form A Relative to the Control SampleSodium Dioctyl Sulfosuccinate125.61 0Sodium Lauryl Sulfate135.82 0Igepal.(R). CO-6301323 8Pluronic.(R). F68NF143.21 10Hydroxypropyl Cellulose0.3421 72Hydroxypropyl Methylcellu-lose0.4471 97Polyvinylpyrrolidone168.32 1071Literature Value (Johnson, Barbara A., Kreuter, Jorg and Zografi,George, "Effects of Surfactants and Polymers on Advancing and Receding Contact Angles" Colloids and Surfaces, 17(1986) 325-342.)2Surface tension of an aqueous solution of the polymer at the concentration used in the suspensiondetermined with a Kruss Tensiometer using the Wilhemy plate method at room temperature.3GAF Chemicals Corp.,Technical Bulletin 2303-015R2 (1986) This example showed that additives which are surface active such as hydroxy-propyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate and sodium dioctyl sul-fosuccinate are effective in slowing the conversion of form F to the dihydrate form. The anionic surfactants, sodiumlauryl sulfate and sodium dioctyl sulfosuccinate, are also shown as effective for inhibiting conversion of a second non-dihydrate azithromycin form (form M). The cellulosic polymers, hydroxypropyl cellulose and hydroxypropyl methylcel-lulose, and the polyoxyethylene-polyoxypropylene copolymer Pluronic.(R). F68NF and the nonionic surfactant nonyl-phenoxy polyoxyethylene Igepal.(R). CO-630 were also found to slow the conversion of non-dihydrate azithromycinform M. The effectiveness of these additives is related to their surface activity as shown in Tables 10 and 11.

With water, hydroxypropyl cellulose, Time= 24h, T= 20 °C , Conversion of starting material



With water, hydroxypropyl methylcellulose, Time= 24h, T= 20 °C , Conversion of starting material



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O O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH


Example Name 3.a; 3.bExample 3: Preparation of azithromycin:; (a) Preparation of boron complex of cyclic amine of Formula III:; 6,9-miinoether (Formula-II) (100 g) was suspended in water (1.0 lit). The reaction mixture was cooled to 0-5.deg.C. To theresulting reaction mixture, chilled aqueous solution of sodium borohydride (18.0 g in 200ml water) was added at tem-perature between 0-5.deg.C and pH was maintained between 6.0 -8.0 with formic acid. After completion of the boro-hydride addition, the reaction mixture was stirred at 0-50.deg.C for 1 hr and then at room temperature for 10 hrs. ThepH was adjusted to 9.5 with sodium hydroxide solution and then aqueous layer was extracted with chloroform (300mlx 2). The combined chloroform extracts containing title compound a) was taken for the next step.; (b); The pH of thechloroform extract was adjusted to 5.0 to 5.5 with formic acid (17.0 g) and formaldehyde (17.0 g) and the resultant masswas refluxed for 10 hr. After completion of the reaction, water (500 ml) was added and the pH was brought to 4.0 withhydrochloric acid. The chloroform layer was separated and to the aqueous layer, methanol (500 ml) was added. Theresulting reaction mixture was cooled to -10 to - 2O0C and the pH was adjusted to 1.0 with hydrochloric acid. Thenreaction mixture was basified with sodium hydroxide and extracted with chloroform (300 ml x 2). The combined chloro-form extracts were concentrated to dryness and crystallized with isopropyl alcohol/ water or acetonitrile / water mixtureto get the title compound. Yield: 65 g. Purity: 98.0percent (By HPLC)

Stage 1: With sodium tetrahydroborate, formic acid in water, Time= 11h, T= 0 - 50 °C , pH= 6 - 8Stage 2: With sodium hydroxide in water, pH= 9.5Stage 3: With hydrogenchloride, sodium hydroxide, formic acid, Product distribution / selectivity, more than 3 stages


O

O

O

B (v3)

N

HO

O

O

HO O

O

O

O

OH

OH

N

O HO

O

O

OH

O

O O

N

N

O

HO

OH

HO

O H

H 2


Reaction Steps: 21: 70.5 percent / H2SO4 / acetonitrile; H2O / 0.5 h / 15 °C / pH 22: 84.2 percent / water / acetone / 24 h / Ambient temperatureWith sulfuric acid, water in water, acetone, acetonitrile








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O O

O

O

N HO

O

O

O

N

HO

O

HO

OH

Z

O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH


Reaction Steps: 21: nitromethane / 2 h / 100 °C2: 1.) NaBH4 / 1.) ethylene glycol, 0 deg C -> room temperature; room temperature, 5 h, 2.) H2O, CHCl3With sodium tetrahydroborate in nitromethane


O OH O

H

O

OH

O

O

OH

O

O

O

HN N

O

HO

OH

OH

OH

OH

O

OH

O

O

OH

O

O

O

N N

O

HO

OH

OH

H 2 O

3

10 10


70 - 94 % Example Name 1; 2; 3; 4EXAMPLE 1; Azaerythromycin 100 g (96.0percent) is suspended in Isopropanol (300 ml) and the temperature is raisedto 60-75.deg. C. Methylating solution (23 ml formic acid (Assay=99percent) and 23 ml formaldehyde 35percent) areadded over a period of 4-5 hours. The mixture is stirred for 12 hrs and then cooled to 40.deg. C. The sodium hydroxidesolution (25percent w/v, 60-70 ml) is added in the reaction mixture and stirred for 20 minutes. Aqueous layer is separatedand extracted with 75 ml isopropanol. Combined organic layer (Isopropanol) is distilled out up to foamy materials.Isopropanol (300 ml) is added and the reaction mass is heated to 45-50.deg. C. Combine organic layer is clarified byfiltration. To the filtered isopropanol solution, water (450 ml) is added to precipitate azithromycin monohydrate isopro-panol clathrate. The mass is stirred for 6 hrs at 25 to 30.deg. C. The resulting product is filtered and washed with 50:50mixture of isopropanol-water. The product is dried under vacuum (1 to 10 mm Hg) at 25-50.deg. C. temp for 2-10 hrs.Yield 89.0 gms (89percent) Isopropanol: 3.26percent. Water: 2.91percent.; EXAMPLE 2; Azaerythromycin 100 g(96.0percent) is suspended in Isopropanol (300 ml) and the temperature is raised to 60-65.deg. C. Methylating solution(23.0 ml formic acid (Assay=99percent) and 23 ml formaldehyde 35percent) are added over a period of 4-5 hours. Themixture is stirred for 12 hrs and then the mass is cooled to 40.deg. C. The sodium hydroxide solution (25percent w/v,60-70 ml) is added in the reaction mixture and stirred for 20 minutes. Aqueous layer is separated and extracted with75 ml isopropanol. Combined organic layer (Isopropanol) is clarified by filtration. Water (570 ml) is added in 15-30minutes and the reaction mass is stirred for 6-12 hrs at 25 to 30.deg. C. temp. The resulting product is filtered andwashed with 50:50 mixture of isopropanol-water. The product is dried under vacuum at 45-50.deg. C. temp underreduced pressure. The product is dried under vacuum (1 to 10 mm Hg) at 25-50.deg. C. temp for 2-10 hrs. Yield 94gms (94percent) Isopropanol: 3.19percent Water: 2.5percent; EXAMPLE 3; Azaerythromycin 100 g (89.0percent purity)is suspended in Isopropanol (300 ml) at temperature of 25-30.deg. C. To this solution formic acid (16.6 gms, 2.654mole) and Paraformaldehyde (10.0 gms, 2.45 mole) are added and the temperature is raised up to 65-70.deg. C. Themixture is stirred for 3-6 hrs and the mass is cooled to 40.deg. C. The mixture is stirred for 12 hrs and cooled to 40.deg.C. The sodium hydroxide solution (25percent w/v, 60-70 ml) is added in the reaction mixture and stirred for 20 minutes.Aqueous layer is separated and extracted with 50 ml isopropanol. Combine organic layer (Isopropanol) is clarified byfiltration and distilled isopropanol up to foamy materials., Isopropanol (300 ml) is added and the reaction mass is heated





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to 45-50.deg. C. Combine organic layer is clarified by filtration. To the filtered isopropanol solution, water (400 ml) isadded to precipitate azithromycin monohydrate isopropanol clathrate. The mass is then stirred for 6-12 hrs at 25 to30.deg. C. The resulting product is filtered and washed with 50:50 mixture of isopropanol-water. The product is driedunder vacuum (1 to 10 mm Hg) at 25-50.deg. c. temp for 2-10 hrs. Yield 70.0 gms (70percent) Isopropanol: 3.36percentWater: 2.04percent; EXAMPLE 4; Azaerythromycin 100 g (purity=89percent) is suspended in isopropanol (300 ml) attemperature of 25-35.deg. C. To this solution formic acid (16.6 gms, 2.65 mole) and Paraformaldehyde (10.0 gms, 2.45mole) are added and the temperature of reaction mass is raised to 65-70.deg. C. The mixture is stirred for 3-6 hrs andcooled to 40.deg. C. The sodium hydroxide solution (25percent w/v, 60-70 ml) is added in the reaction mixture andstirred for 20 minutes. Aqueous layer is separated and extracted with 50 ml isopropanol. Combine organic layer (Iso-propanol) is clarified by filtration. To the filtered isopropanol solution, water (400 ml) is added to precipitate azithromycinmonohydrate isopropanol clathrate. The mass is then stirred for 6-12 hrs at 25 to 30.deg. C. The resulting product isfiltered and washed with 50:50 mixture of isopropanol-water. The product is dried under vacuum (1 to 10 mm Hg) at25-50.deg. C. temp for 2-10 hrs. Yield 80 gms (80percent) Isopropanol: 3.14percent Water: 2.56percent

Stage 1:, Time= 3 - 17h, T= 60 - 75 °CStage 2: With sodium hydroxide, water, Time= 0.333333h, T= 40 °C , Product distribution / selectivity

Patent; ALEMBIC LIMITED; US2006/19908; (2006); (A1) EnglishView in Reaxys

O OH O

H HO

O

O

N

O

O

HO O

O

O

O

HO

OH

N

O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH


With sodium tetrahydroborate, 1.) ethylene glycol, 0 deg C -> room temperature; room temperature, 5 h, 2.) H2O,CHCl3, Multistep reaction


O

OH

O O

OH O

O

O

N

N

O

HO

OH

OH

O H H

2


95 % Example Name 1DTo 10 gm of Azithromycin dihydrate, 30 ml acetone was added for 30 minutes with stirring till the clear solution obtained.0.3 gm charcoal was added to this solution and the mixture was stirred for 30 minutes and subsequently filtered. Tothe filtrate, 180 ml of water was added at 50.deg. to 55.deg. C within 12 hour. The aqueous filtrate was cooled to roomtemperature and then chilled to 0.deg. to 5.deg. C. Azithromycin dihydrate was filtered from the aqueous filtrate andwashed with chilled water (0.deg. to 5.deg. C). Azithromycin dihydrate was dried at 65.deg. C. The yield and purity ofAzithromycin dihydrate was 95 percent and 100 percent.Azithromycin dihydrate was characterized by IR (Refer Figure2 of the Accompanying drawing)






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Stage 1: With carbon in water, acetone, Time= 1hStage 2: in water, acetone, Time= 12h, T= 0 - 55 °C , Purification / work up


Example Name 5Example Title Azithromycin DihydrateEXAMPLE 5Azithromycin DihydrateThe title product, 0.5 Kg, prepared in Example 4, was dissolved in water, making the solution acidic (pH of 2.5 to 5.0)with dilute hydrochloric acid.After 20 minutes stirring the pH was raised with dilute sodium hydroxide and the solution was stirred for twelve hours.The product was crystallized as a white crystalline material in high purity. Yield: 0.48 Kg.

Patent; Wockhardt Limited; US2003/139583; (2003); (A1) EnglishView in Reaxys

Example Title Preparation of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate.Method A25 g of crystalline azithromycin monohydrate are dissolved in 130 ml of tert-butanol heating at 30.deg. C.This solution is filtered and 130 ml of water are added over 6 h.The resulting mixture is taken to pH=11 by addition of NaOH 2N, cooled down below 10.deg. C. and subsequentlystirred for 48-72 h.The crystals are collected by filtration and dried (80 mm Hg/25.deg. C.) to yield 15 g of azithromycin dihydrate.

Patent; Astur-Pharma, S.A.; US6451990; (2002); (B1) EnglishView in Reaxys

Example Title Preparation of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate.Method B25 g of crystalline azithromycin monohydrate are dissolved in 50 ml of tert-butanol heating at 30.deg. C.This solution is filtered and discharged over a mixture of 500 ml of petroleum ether and 20 ml of water.The resulting mixture is cooled down below 10.deg. C. and subsequently stirred for 48-72 h.The crystals are collected by filtration and dried (80 mm Hg/25.deg. C.) to yield 12 g of azithromycin dihydrateIR(KBr), 1H-NMR (CDCl3), 13C-NMR (CDCl3), m/e, TLC and HPLC are identical to those of the previous example.


Example Name 1Example Title Non-Hygroscopic Azithromycin Dihydrate Method AEXAMPLE 1Non-Hygroscopic Azithromycin Dihydrate Method AThe hygroscopic monohydrate of Preparation 1 (100 g; water-content:3.1percent), tetrahydrofuran (220 ml) and dia-tomaceous earth (5 g) were combined in a 500 ml Erlenmyer flask, stirred for 30 minutes and filtered with 20 ml oftetrahydrofuran wash.The combined filtrate and wash was transferred to a 3 liter round bottom flask.The solution was stirred vigorously and H2 O (2.0 ml) was added.After 5 minutes, hexane (1800 ml) was added over 5 minutes, with continued vigorous stirring.Following an 18 hour granulation period, title product was recovered by filtration with 1*10 ml hexane wash, and driedin vacuo to 4.6+-0.2percent H2 O by Karl Fischer, 89.5 g.


Example Name 1.BExample Title Method BMethod BThe hygroscopic monohydrate of Preparation 1 (197.6 g) and tetrahydrofuran (430 ml) were charged to a reactor andthe mixture stirred to achieve a milky white solution.Activated carbon (10 g) and diatomaceous earth (10 g) were added and the mixture stirred for 15 minutes, then dilutedwith 800 ml of hexane and filtered with suction over a pad of diatomaceous earth with 250 ml of hexane for wash.







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The combined filtrate and wash was diluted to 2500 ml with hexane and warmed to 34.deg. C. With stirring, 24.7 ml ofH2 O was added.The mixture was allowed to cool to room temperature, granulated for five hours and title product recovered and driedas in Method A, 177.8 g.The dihydrate melts sharply at 126.deg. C. (hot stage, 10.deg./minute); differential scanning calorimetry (heating rate,20.deg. C./minute) shows an endotherm at 127.deg. C.; thermal gravimetric analysis (heating rate 30.deg. C./minute)shows a 1.8percent weight loss at 100.deg. C. and a 4.3percent weight loss at 150.deg. C.; ir (KBr) 3953, 3553, 3488,2968, 2930, 2888, 2872, 2827, 2780, 2089, 1722, 1664, 1468, 1426, 1380, 1359, 1344, 1326, 1318, 1282, 1270, 1252,1187, 1167, 1157, 1123, 1107, 1082, 1050, 1004, 993, 977, 955, 930, 902, 986, 879, 864, 833, 803, 794, 775, 756,729, 694, 671, 661, 637, 598, 571, 526, 495, 459, 399, 374, 321 and 207 cm-1; [alpha]D 26 =-41.4.deg. (c=1, CHCl3)Anal Calcd. for C38 H72 N2 O12.2H 2 O:C, 58.14; H, 9.77; N, 3.57; OCH3, 3.95; H2 O, 4.59.


Example Name 1Example Title EXAMPLE 1EXAMPLE 1Preparation of azithromycin dihydrate.5g of crude azithromycin, prepared as described in EP 9803945.4, was dissolved in 22.6 ml of water and 2.4 ml ofhydrochloric acid (6N) at a temperature of from 20.deg.C to 25.deg.C.To this solution was added 25 ml of acetone and 2.8 ml of 20percent (w/v) aqueous sodium hydroxide solution to adjustthe pH to 9.8.After stirring for 5 hours at a temperature of from 20.deg.C to 25.deg.C the suspension was cooled to from 5.deg.C to0.deg.C and stirred for 1 hour at this temperature.The resulting solid was collected by filtration, washed with water (3 times 5 ml of water cooled at 5.deg.C) and dried at35-40.deg.C to give azithromycin dihydrate (3.3g).

Patent; HOVIONE INTER LTD.; EP941999; (1999); (A2) EnglishView in Reaxys

Example Name 2Example Title EXAMPLE 2EXAMPLE 2Preparation of azithromycin dihydrate.5g of crude azithromycin was dissolved in 12.6 ml of water and 2.4 ml of hydrochloric acid (6N) at a temperature offrom 20.deg.C to 25.deg.C.To this solution was added 35 ml of acetone and 2.8 ml of 20percent (w/v) aqueous sodium hydroxide solution to adjustthe pH to 9.8.After stirring for 5 hours at a temperature of from 20.deg.C to 25.deg.C the suspension was cooled to from 5.deg.C to0.deg.C and stirred for 1 hour at this temperature.The resulting solid was collected by filtration, washed with water (3 times 5 ml of water cooled at 5.deg.C) and dried at35-40.deg.C to give azithromycin dihydrate (2.6g).


Example Name 3Example Title EXAMPLE 3EXAMPLE 3Preparation of azithromycin dihydrate.5g of crude azithromycin was dissolved in 32.6 ml of water and 2.4 ml of hydrochloric acid (6N) at a temperature offrom 20.deg.C to 25.deg.C.To this solution was added 15 ml of acetone and 2.8 ml of 20percent (w/v) aqueous sodium hydroxide solution to adjustthe pH to 9.8.After stirring for 29 hours at a temperature of from 20.deg.C to 25.deg.C the suspension was cooled to from 5.deg.Cto 0.deg.C and stirred for 1 hour at this temperature.The resulting solid was collected by filtration, washed with water (3 times 5 ml of water cooled at 5.deg.C) and dried at35-40.deg.C to give azithromycin dihydrate (4.6g).

Patent; HOVIONE INTER LTD.; EP941999; (1999); (A2) English





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View in Reaxys

Example Name 5Example Title EXAMPLE 5EXAMPLE 5Conversion of azithromycin monohydrate to azithromycin dihydrate.Azithromycin monohydrate (5g) was suspended in 50 ml of water/acetone (30:70 by weight) and stirred for 24 hoursat 20-25.deg.C.The solid was collected by filtration, and dried at 35-40.deg.C to give azithromycin dihydrate (4.8g).


Example Name 1.AExample Title Method AMethod AThe hygroscopic monohydrate of Preparation 1 (100 g; water-content:3.1percent), tetrahydrofuran (220 ml) and dia-tomaceous earth (5 g) were combined in a 500 ml Erlenmyer flask, stirred for 30 minutes and filtered with 20 ml oftetrahydrofuran wash.The combined filtrate and wash was transferred to a 3 liter round bottom flask.The solution was stirred vigorously and H2O (2.0 ml) was added.After 5 minutes, hexane (1800 ml) was added over 5 minutes, with continued vigorous stirring.Following an 18 hour granulation period, title product was recovered by filtration with 1 x 10 ml hexane wash, and driedin vacuo to 4.6+-0.2percent H2O by Karl Fischer, 89.5 g.


Example Name 1.BExample Title Method BMethod BThe hygroscopic monohydrate of Preparation 1 (197.6 g) and tetrahydrofuran (430 ml) were charged to a reactor andthe mixture stirred to achieve a milky white solution.Activated carbon (10 g) and diatomaceous earth (10 g) were added and the mixture stirred for 15 minutes, then dilutedwith 800 ml of hexane and filtered with suction over a pad of diatomaceous earth with 250 ml of hexane for wash.The combined filtrate and wash was diluted to 2500 ml with hexane and warmed to 34.deg.C. With stirring, 24.7 ml ofH2O was added.The mixture was allowed to cool to room temperature, granulated for five hours and title product recovered and driedas in Method A, 177.8 g.The dihydrate melts sharply at 126.deg.C (hot stage, 10.deg./minute); differential scanning calorimetry (heating rate,20.deg.C/minute) shows an endotherm at 127.deg.C; thermal gravimetric analysis (heating rate 30.deg.c/minute)shows a 1.8percent weight loss at 100.deg.C and a 4.3percent weight loss at 150.deg.C; ir (KBr) 3953, 3553, 3488,2968, 2930, 2888, 2872, 2827, 2780, 2089, 1722, 1664, 1468, 1426, 1380, 1359, 1344, 1326, 1318, 1282, 1270, 1252,1187, 1167, 1157, 1123, 1107, 1082, 1050, 1004, 993, 977, 955, 930, 902, 986, 879, 864, 833, 803, 794, 775, 756,729, 694, 671, 661, 637, 598, 571, 526, 495, 459, 399, 374, 321 and 207 cmmin 1; [alpha] [26/D ] = -41.4.deg. (c=1,CHCl3).Anal. Calcd. for C3 8H7 2N2O1 2.2H2O:C, 58.14; H, 9.77; N, 3.57; OCH3, 3.95; H2O, 4.59.Found:C, 58.62; H, 9.66; N, 3.56; OCH3, 4.11; H2O, 4.49.


Example Name 1.AExample Title Method AMethod AThe hygroscopic monohydrate of Preparation 1 (100 g; water-content:3.1percent), tetrahydrofuran (220 ml) and dia-tomaceous earth (5 g) were combined in a 500 ml Erlenmyer flask, stirred for 30 minutes and filtered with 20 ml oftetrahydrofuran wash.The combined filtrate and wash was transferred to a 3 liter round bottom flask.The solution was stirred vigorously and H2O (2.0 ml) was added.After 5 minutes, hexane (1800 ml) was added over 5 minutes, with continued vigorous stirring.






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Following an 18 hour granulation period, title product was recovered by filtration with 1*10 ml hexane wash, and driedin vacuo to 4.6+-0.2percent H2O by Karl Fischer, 89.5 g.


Example Name 1.BExample Title Method BMethod BThe hygroscopic monohydrate of Preparation 1 (197.6 g) and tetrahydrofuran (430 ml) were charged to a reactor andthe mixture stirred to achieve a milky white solution.Activated carbon (10 g) and diatomaceous earth (10 g) were added and the mixture stirred for 15 minutes, then dilutedwith 800 ml of hexane and filtered with suction over a pad of diatomaceous earth with 250 ml of hexane for wash.The combined filtrate and wash was diluted to 2500 ml with hexane and warmed to 34.deg. C. With stirring, 24.7 ml ofH2O was added.The mixture was allowed to cool to room temperature, granulated for five hours and title product recovered and driedas in Method A, 177.8 g.


O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH


100 % Example Name 11-16

Purification / work up

Patent; Pliva Pharmaceutical Industry, Incorporated; US2004/92460; (2004); (A1) EnglishView in Reaxys

98% Example Name 6Example Title N-Methyl-11-aza-10-deoxo-10-dihydroerythromycin AEXAMPLE 6N-Methyl-11-aza-10-deoxo-10-dihydroerythromycin AA solution of N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A desosaminyl-N-oxide (15 mg) in ethanol (5 ml) washydrogenated at 2 psi using 5 mg 5percent Pd-C catalyst for 3 hours.Filtration of the catalyst and solvent removal in vacuo produced the title compound (98percent yield) as a colorlessfoam.Its 1 Hnmr and TLC Rf values were identical to those of the product of Example 3.


95 % Example Name 1DExample 1 D; Purification of Azithromycin dihydrate; To 10 gm of Azithromycin dihydrate, 30 ml acetone was addedfor 30 minutes with stirring till the clear solution obtained. 0.3 gm charcoal was added to this solution and the mixturewas stirred for 30 minutes and subsequently filtered. To the filtrate, 180 ml of water was added at 50.deg. to 55.deg.C within 12 hour. ThI aqueous filtrate was cooled to room temperature and then chilled to 0.deg. to 5.deg. C. Azithro-mycin dihydrate was filtered from the aqueous filtrate and washed with chilled water (0.deg. to 5.deg. C). Azithromycindihydrate was dried at 65.deg. C. The yield and purity of Azithromycin dihydrate was 95 percent and 100 percent.Azi-thormycin dihydrate was characterized by IR (Refer Figure 2 of the Accompanying drawing).







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in water, acetone, Time= 13h, T= 0 - 55 °C , Purification / work up


Example Name 2.BExample Title 2B2BAzithromycin dihydrate is slowly added to one volume of warm ethanol, about 70.deg. C., and stirred to completedissolution at 65 to 70.deg. C.The solution is allowed to cool gradually to 2-5.deg. C. and ethanol volume may be reduced by vacuum distillation.Seeds of Form F 1-2percent wt may be introduced to facilitate the crystallization.After stirring up to 2 hours the crystalline solids are collected by vacuum filtration.The isolation of the crystals yields substantially pure form F azithromycin, form F azithromycin substantially free of formG azithromycin and form F azithromycin substantially free of azithromycin dihydrate.

Patent; Li, Zheng J.; Trask, Andrew V.; US2003/162730; (2003); (A1) EnglishView in Reaxys

Example Name 6Example Title Preparation of Form NExample 6Preparation of Form NTwo volumes of ethanol and 2 volumes of isopropanol were added to a reaction vessel and heated to 50.deg. C.Azithromycin form A was added with stirring to the heated ethanol/isopropanol mixture to yield a clear solution.The reaction vessel was charged with 2 volumes distilled water (ambient temperature).Stirring was continued at 50.deg. C. and solid form N azithromycin precipitated after approximately 1 hr.Heating was discontinued 5 hours after the addition of the water.The slurry was allowed to cool to ambient temperature.Precipitated form N azithromycin was collected by filtration and dried for 4 hours in vacuum oven at 45.deg. C.


Example Name 7Example Title Preparation of Amorphous AzithromycinExample 7Preparation of Amorphous AzithromycinCrystalline form A azithromycin was heated to 110-120.deg. C. in an oven for overnight under vacuum.The amorphous solids were collected and stored with desiccant as needed.


Example Name 6Example Title Anhydrous AzithromycinEXAMPLE 6Anhydrous AzithromycinThe azithromycin dihydrate, prepared in Example 5, or the azithromycin monohydrate, prepared in Example 4, about500 g, was dissolved in isopropanol, 3 L.The solution was heated and the alcohol was distilled to remove the water.After the solvent was removed the residue was dried under vacuum to provide the anhydrous azithromycin.Yield 470 g; Purity>=96percent.

Patent; Wockhardt Limited; US2003/139583; (2003); (A1) EnglishView in Reaxys

In a preferred embodiment of the invention the antibiotic is selected from:Erythromycin;Roxithromycin;Clarithromycin;Azithromycin;Dirithromycin; and







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Patent; Schickaneder, Helmut; Nikolopoulos, Aggelos; Hermann, Gesine; US2001/31736; (2001); (A1) EnglishView in Reaxys

claim 1wherein the antibiotic is selected from:Erythromycin;Roxithromycin;Clarithromycin;Azithromycin;Dirithromycin; and

Patent; Schickaneder, Helmut; Nikolopoulos, Aggelos; Hermann, Gesine; US2001/31736; (2001); (A1) EnglishView in Reaxys

Example Title General Isolation Procedure (Solvent May Form a Two Phase System With Water)General Isolation Procedure (Solvent May Form a Two Phase System With Water)A reaction mixture as obtained in one of the Examples above as specified in TABLE 2 below under "Reaction Example"is cooled to room temperature and treated with 40 ml of solvent as specified in TABLE 2 below under "Solvent", 40 mlof water and 20percent sulfuric acid to obtain a pH of the mixture of ca. 4.The mixture obtained is stirred for ca.15 minutes and the phases are separated.The aqueous phase obtained is extracted with 25 ml of solvent as specified in TABLE 2 below under "Solvent".The aqueous phase is treated with 20percent sodium hydroxide to obtain a pH 9 and the mixture obtained is stirred forca.15 minutes and extracted with 25 ml of solvent as specified in TABLE 2 below under "Solvent".The organic phase is dried over anhydrous sodium sulphate and the sodium sulphate is filtrated off.The organic solvent is evaporated off.Azithromycin in a yield as specified in TABLE 2 below under "Yield (in gram)" in percent of theory as specified in TABLE2 below under "percent of theory" is obtained.


Example Name 1Example Title EXAMPLE 1EXAMPLE 1To a solution of 2 g (2.7 mmoles) of the imino ether of erythromycin A, prepared by the usual techniques, in 20 ml ofacetic acid, there were added 0.03 g (0.38 mmoles) of sodium acetate and 0.5 g of wet 5percent Rh/C (11.25 mg Rh).The mixture was then hydrogenated at a pressure of 70 bar and at 40.deg. C. for 3 hours.At the end of this period, 27 ml of an aqueous solution containing 37percent formaldehyde (0.36 moles) were addedunder atmospheric pressure and at room temperature, and the mixture hydrogenated at 40 bar and at a temperatureof 40.deg. C. for 20 hours.The catalyst was filtered off and the filtrate evaporated until an oil was obtained.To the oil so obtained, 45 ml of water were added, and the pH of the solution was adjusted to 9.3 with 4N NaOH.After stirring for 2 hours at room temperature, the solid was filtered, washed with water, and dried, yielding 1.2 g ofcrude azithromycin with a purity of 97percent after recrystallization.

Patent; Hovione Inter Ltd.; US6013778; (2000); (A1) EnglishView in Reaxys

Example Name 2Example Title EXAMPLE 2EXAMPLE 2To a solution of 4 g (5.4 mmoles) of the imino ether of erythromycin A, prepared by the usual techniques, dissolved in20 ml of acetic acid, 1 g wet 5percent Rh/C (22.5 mg Rh) was added.The mixture was hydrogenated at 60 bar and at a temperature of 40.deg. C. for 5 hours.At the end of this period, 22.5 ml of an aqueous solution containing 37percent formaldehyde (0.3 moles) were addedunder atmospheric pressure and at room temperature, and the mixture was then hydrogenated at 40 bar and at atemperature of 40.deg. C. for 20 hours.The catalyst was filtered off and the filtrate evaporated until an oil was obtained.To this oil, 90 ml of water were added, and the pH of the solution was adjusted to 9.4 with 4N NaOH.After stirring for 2 hours at room temperature, the solid was filtered, washed with water, and dried, yielding 2 g of crudeazithromycin with a purity of 97percent after recrystallization.






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Example Name 3Example Title EXAMPLE 3EXAMPLE 3To a solution of 8 g (10.9 mmoles) of the imino ether of erythromycin A, prepared by the usual techniques, in 32 ml ofacetic acid and 8 ml of water, there were added 8 g of wet 5percent Rh/C (180 mg Rh).The mixture was then hydrogenated at 70 bar and at room temperature for 2 hours.At the end of this period, 40 ml of an aqueous solution containing 37percent formaldehyde (0.54 moles) were added,and the mixture was hydrogenated at 40 bar and at a temperature of 40-45.deg. C. for 20 hours.The catalyst was filtered off, and the pH of the filtrate was adjusted to 9.4 with 4N NaOH.After stirring for 2 hours at room temperature, the solid was filtered, washed with water, and dried, yielding 7 g of crudeazithromycin with a purity of 95percent after recrystallization.


Example Name 4Example Title EXAMPLE 4EXAMPLE 4To a solution of 4 g (5.4 mmoles) of the imino ether of erythromycin A, prepared by the usual techniques, in 4 ml ofacetic acid and 16 ml of water, were added 4 g of wet 5percent Rh/C (90 mg Rh).The mixture was hydrogenated at 70 bar and room temperature for 2 hours.At the end of this period, 25 ml of an aqueous solution containing 37percent formaldehyde (0.34 moles) was addedunder atmospheric pressure at room temperature and the mixture was hydrogenated at 40 bar and at a temperatureof 40-45.deg. C. for 24 hours.The catalyst was filtered off, and the pH of the filtrate adjusted to 9.4 with 4N NaOH.After stirring for 2 hours at room temperature, the precipitate was filtered off, washed with water, and dried, yielding 2.8g of crude azithromycin with a purity of 98percent after recrystallization.


Example Name 5Example Title EXAMPLE 5EXAMPLE 5To a solution of 8 g (10.9 mmoles) of the imino ether of erythromycin A, prepared by the usual techniques, in 24 ml ofacetic acid, there were added 8 g of wet 5percent Rh/C (180 g Rh).The mixture was hydrogenated at 70 bar and at room temperature for 2 hours.At the end of this period, 50 ml of an aqueous solution containing 37percent formaldehyde (0.67 moles) were addedunder atmospheric pressure at room temperature, and the mixture was hydrogenated at 40 bar and 40-45.deg. C. for24 hours.The catalyst was filtered off, and the pH of the filtrate was adjusted to 9.5 with 4N NaOH.After stirring for 2 hours at room temperature, the solids were filtered, washed with water, and dried, yielding 6.1 g ofcrude azithromycin with a purity of 98percent after recrystallization.


Example Name 6Example Title EXAMPLE 6EXAMPLE 6To a solution of 4 g (5.4 mmoles) of the imino ether of erythromycin A, prepared by the usual techniques, in 18 ml ofacetic acid and 2 ml of water, there were added 2 g of wet 5percent Rh/C (45 mg Rh).The mixture was then hydrogenated at 70 bar and at room temperature for 2 hours.At the end of this period, 35 ml of an aqueous solution containing 37percent formaldehyde (0.47 moles) were addedunder atmospheric pressure at room temperature, and the pH was adjusted between 3 and 4 with 4N NaOH.The mixture was hydrogenated at 40 bar and at a temperature of 40-45.deg. C. for 24 hours.The catalyst was filtered off, and the pH of the filtrate was adjusted to 9.4 with 4N NaOH.After stirring for 2 hours at room temperature, the solid was filtered, washed with water, and dried, yielding 2.7 g ofcrude azithromycin with a purity of 96percent after recrystallization.

Patent; Hovione Inter Ltd.; US6013778; (2000); (A1) English






49/55 2011-04-19 08:56:52

View in Reaxys

Example Name 7Example Title EXAMPLE 7EXAMPLE 7To a solution of 8 g (10.9 mmoles) of the imino ether of erythromycin A, prepared by the usual techniques, in 8 ml ofacetic acid and 32 ml of water, there were added 8 g of wet 5percent Rh/C (180 mg Rh).The mixture was then hydrogenated at 70 bar and at 40.deg. C. for 2 hours.At the end of this period, 10 g (0.33 moles) of para-formaldehyde was added under atmospheric pressure at roomtemperature, and the pH of the reaction mixture was adjusted to 4 with NaOH.Hydrogenation was carried out at a pressure of 40 bar and at a temperature of 40-45.deg. C. for 24 hours.The catalyst was filtered off, and the pH of the reaction mixture was adjusted to 9.2 with NaOH 4N.After stirring for 2 hours at room temperature, the solids were filtered, washed with water, and dried, yielding 4.98 g ofcrude azithromycin with a purity of 97percent after recrystallization.


Example Name 3Example Title N-Methyl-11-aza-10-deoxo-10-dihydroerythromycin AEXAMPLE 3N-Methyl-11-aza-10-deoxo-10-dihydroerythromycin AA solution of the crude product of Example 2, comprising N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A deso-saminyl-N-oxide and N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A bis-N-oxide (4.36 g), in 150 ml of absoluteethanol was hydrogenated on a Parr apparatus (3.52 kg/m2; 8.0 g 10percent palladium on carbon catalyst; ambienttemperature) for 11/4 hours.The catalyst was filtered, and the resulting filtrate was evaporated to dryness, affording a colorless foam (4.3 g).The crude product was taken up in methylene chloride (100 ml) and then stirred with water (100 ml) while the pH of themixture was adjusted to 8.8.The organic and aqueous layers were separated.The aqueous layer was then extracted twice with 50 ml portions of methylene chloride.The three organic extracts were combined, dried over anhydrous sodium sulfate and evaporated to afford a colorlessfoam (3.0 g).The entire sample was dissolved in 11 ml of warm ethanol, and water was added until the solution became slightlyturbid.Upon standing overnight, 1.6 g of the title product crystallized from solution; m.p.136.deg. C., dec.A recrystallization by the same procedure raised the melting point to 142.deg. C., dec. 1 Hnmr (CDCl3) delta 2.31 [6H,s, (CH3)2 N-], 2.34 STR8 13 Cnmr [CDCl3, (CH3)4 Si internal standard] ppm 178.3 (lactone, C=0), 102.9 and 94.8 (C-3,C-5), 41.6 STR9 40.3 [(CH3)2 -N-]; MS: m/e 590, 432, 158.


0.45 g(82.4%)

Example Name 1Example Title N-methyl-11-aza-10-deoxo-10-dihydro erythromycin AEXAMPLE 1N-methyl-11-aza-10-deoxo-10-dihydro erythromycin ATo a solution of 0.54 g (0.000722 mole) of 11-aza-10-deoxo-10-dihydro erythromycin A in 20 ml of CHCl3 there wereadded, while stirring, 0.0589 ml (0.000741 mole) of formaldehyde (approx. 35percent w./w.) and 0.0283 g (0.000735mole) of formic acid (approx. 98 to 100percent w./w.).The reaction mixture was stirred for 8 hours while heating under reflux, then cooled to ambient temperature, whereuponthere were added 15 ml of water (pH 5.8).The pH of the reaction mixture was adjusted to 5.0 by means of 2N HCl, whereupon the chloroform layer was separated.To the aqueous part there was added 15 ml of CHCl3, the pH of the reaction suspension was adjusted to 7.5 by meansof 20percent w./w. of NaOH, the layers were separated and subsequently the aqueous layer was extracted three timeswith 15 ml of CHCl3.The combined chloroform extracts having a pH of 7.5were dried over K2 CO3 and evaporated under reduced pressure, yielding 0.45 g (82.4percent) of N-methyl-11-aza-10-deoxo-10-dihydro erythromycin A, m.p. 113.deg.-115.deg. C.[α]D 20 =-37.0 (1percent in CHCl3); M30 =748.





50/55 2011-04-19 08:56:52

Patent; Sour Pliva farmaceutska, kemijska prehrambena i kozmeticka industrija, n.sol.o.; US4517359; (1985);(A1) EnglishView in Reaxys

Example Name 5Example Title 9-Deoxo-9a-methyl-9a-aza-9a-homoerythromycin APREPARATION 59-Deoxo-9a-methyl-9a-aza-9a-homoerythromycin ABy the procedure of Example 10 above, title product of the preceding Preparation (21.1 g., 0.0287 moles) was convertedto present title product, initially isolated as a white foam, crystallized from hot ethanol/H2 O, 18.0 g., mp 136.deg. C.


Example Name 5Example Title N-Methyl-11-aza-10-deoxo-10-dihydroerythromycin AEXAMPLE 5N-Methyl-11-aza-10-deoxo-10-dihydroerythromycin AA solution of crude product of Example 2 comprising N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A desosa-minyl-N-oxide and N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A bis-N-oxide (10.0 g) in 150 ml of absoluteethanol was hydrogenated on a Parr apparatus [3.52 kg/m2; 15 g of Raney-Nickel catalyst (water-wet sludge); ambienttemperature] for 11/2 hours.Work-up as described in Example 3 afforded 8.5 g of the title product, with TLC Rf values identical to those of Example3.


Example Name 1Example Title EXAMPLE 1EXAMPLE 1To a solution of 2 g (2.7 mmoles) of the imino ether of erythromycin A, (prepared by the usual techniques) in 20 ml ofacetic acid, there was added 0.03 g (0.38 mmoles) of sodium acetate and 0.5 g of wet 5percent Rh/C (11.25 mg Rh).The mixture was then hydrogenated at a pressure of 70 bar and at 40.deg.C for 3 hours.At the end of this period, 27 ml of an aqueous solution containing 37percent formaldehyde (0.36 moles) was addedunder atmospheric pressure and at room temperature, and the mixture hydrogenated at 40 bar and at a temperatureof 40.deg.C for 20 hours.The catalyst was filtered off and the filtrate evaporated until an oil was obtained.To the oil so obtained, 45 ml of water was added, and the pH of the solution was adjusted to 9.3 with NaOH 4N.After stirring for 2 hours at room temperature, the solid was filtered, washed with water, and dried, yielding 1.2 g ofcrude azithromycin with a purity of 97percent after recrystallization.


Example Name 2Example Title EXAMPLE 2EXAMPLE 2To a solution of 4 g (5.4 mmoles) of the imino ether of erythromycin A, (prepared by the usual techniques) in 20 ml ofacetic acid, there was added 1 g of wet 5percent Rh/C (22.5 mg Rh).The mixture was hydrogenated at 60 bar and at a temperature of 40.deg.C for 5 hours.At the end of this period, 22.5 ml of an aqueous solution containing 37percent formaldehyde (0.3 moles) was addedunder atmospheric pressure and at room temperature, and the mixture was then hydrogenated at 40 bar and at atemperature of 40.deg.C for 20 hours.The catalyst was filtered off and the filtrate evaporated until an oil was obtained.To this oil, 90 ml of water was added, and the pH of the solution was adjusted to 9.4 with NaOH 4N.After stirring for 2 hours at room temperature, the solid was filtered, washed with water, and dried, yielding 2 g of crudeazithromycin with a purity of 97percent after recrystallization.


Example Name 3Example Title EXAMPLE 3







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EXAMPLE 3To a solution of 8 g (10.9 mmoles) of the imino ether of erythromycin A, (prepared by the usual techniques) in 32 ml ofacetic acid and 8 ml of water, there was added 8 g of wet 5percent Rh/C (180 mg Rh).The mixture was then hydrogenated at 70 bar and at room temperature for 2 hours.At the end of this period, 40 ml of an aqueous solution containing 37percent formaldehyde (0.54 moles) was added,and the mixture was hydrogenated at 40 bar and at a temperature of 40-45.deg.C for 20 hours.The catalyst was filtered off, and the pH of the filtrate was adjusted to 9.4 with NaOH 4N.After stirring for 2 hours at room temperature, the solid was filtered, washed with water, and dried, yielding 7 g of crudeazithromycin with a purity of 95percent after recrystallization.


Example Name 4Example Title EXAMPLE 4EXAMPLE 4To a solution of 4 g (5.4 mmoles) of the imino ether of erythromycin A, (prepared by the usual techniques) in 4 ml ofacetic acid and 16 ml of water, there was added 4 g of wet 5percent Rh/C (90 mg Rh).The mixture was hydrogenated at 70 bar and room temperature for 2 hours.At the end of this period, 25 ml of an aqueous solution containing 37percent formaldehyde (0.34 moles) was addedunder atmospheric pressure at room temperature and the mixture was hydrogenated at 40 bar and at a temperatureof 40-45.deg.C for 24 hours.The catalyst was filtered off, and the pH of the filtrate adjusted to 9.4 with NaOH 4N.After stirring for 2 hours at room temperature, the precipitate was filtered off, washed with water, and dried, yielding 2.8g of crude azithromycin with a purity of 98percent after recrystallization.


Example Name 5Example Title EXAMPLE 5EXAMPLE 5To a solution of 8 g (10.9 mmoles) of the imino ether of erythromycin A, (prepared by the usual techniques) in 24 ml ofacetic acid there was added 8 g of wet 5percent Rh/C (180 mg Rh).The mixture was hydrogenated at 70 bar and at room temperature for 2 hours.At the end of this period, 50 ml of an aqueous solution containing 37percent formaldehyde (0.67 moles) was addedunder atmospheric pressure at room temperature, and the mixture was hydrogenated at 40 bar and 40-45 .deg.C for24 hours.The catalyst was filtered off, and the pH of the filtrate was adjusted to 9.5 with NaOH 4N.After stirring for 2 hours at room temperature, the solid was filtered, washed with water, and dried, yielding 6.1 g ofcrude azithromycin with a purity of 98percent after recrystallization.


Example Name 6Example Title EXAMPLE 6EXAMPLE 6To a solution of 4 g (5.4 mmoles) of the imino ether of erythromycin A, (prepared by the usual techniques) in 18 ml ofacetic acid and 2 ml of water, there was added 2 g of wet 5percent Rh/C (45 mg Rh).The mixture was then hydrogenated at 70 bar and at room temperature for 2 hours.At the end of this period, 35 ml of an aqueous solution containing 37percent formaldehyde (0.47 moles) was addedunder atmospheric pressure at room temperature, and the pH was adjusted to from 3 to 4 with NaOH 4N.The mixture was hydrogenated at 40 bar and at a temperature of 40-45 .deg.C for 24 hours.The catalyst was filtered off, and the pH of the filtrate was adjusted to 9.4 with NaOH 4N.After stirring for 2 hours at room temperature, the solid was filtered, washed with water, and dried, yielding 2.7 g ofcrude azithromycin with a purity of 96percent after recrystallization.


Example Name 7Example Title EXAMPLE 7EXAMPLE 7






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To a solution of 8 g (10.9 mmoles) of the imino ether of erythromycin A, (prepared by the usual techniques) in 8 ml ofacetic acid and 32 ml of water, there was added 8 g of wet 5percent Rh/C (180 mg Rh).The mixture was hydrogenated at 70 bar and at 40.deg.C for 2 hours.At the end of this period, 10 g (0.33 moles) of para-formaldehyde was added under atmospheric pressure at roomtemperature, and the pH of the reaction mixture was adjusted to 4 with NaOH.Hydrogenation was carried out at a pressure of 40 bar and at a temperature of 40-45 .deg.C for 24 hours.The catalyst was filtered off, and the pH of the reaction mixture was adjusted to 9.2 with NaOH 4N.After stirring for 2 hours at room temperature, the solid was filtered, washed with water, and dried, yielding 4.98 g ofcrude azithromycin with a purity of 97percent after recrystallization.


Similarly at 75percent and 100percent relative humidity, the water content rose rapidly, but was now maintained at evenhigher levels, 6.6percent and 7.2percent, respectively, for at least 3 days.1.Use of an antiprotozoal effective amount of:azithromycin;4-epi-azithromycin;4-amino-4-deoxy-azithromycin; or4-epi-4amino-4-deoxy-azithromycin;


Example Name 5Example 5: Anhydrous Azithromycin;; Azithromycin (500 gm, moisture content = 2.64percent) was dissolved in di-chloromethane (8.0 Lit). The solution was heated and the solvent was completely removed under vacuum. Acetonitrile(2.5 Lit) was added to the residue so obtained and the reaction mass was gradually cooled to 15 to 2O0C. The resultingslurry was stirred at 15 to 2O0C for three hours and filtered; the solids so obtained were dried under, vacuum to getanhydrous azithromycin. Yield: 325 gm Purity: 99.62percent (by HPLC) Moisture Content: 0.6percent w/w.

in dichloromethane, acetonitrile, Time= 3h, T= 15 - 20 °C , Purification / work up


Example Name C.4Example Title Uncoated Azithromycin PelletsCOMPARATIVE EXAMPLE 4Uncoated Azithromycin PelletsExtruded pellets with the following composition were produced in the same manner as Comparative Example 1:

Patent; Gruenenthal GmbH; US2010/68290; (2010); (A1) EnglishView in Reaxys

Example Name 12


O

OH

O O

OH O

O

O

N

N

O

HO

OH

OH

O H H

Rx-ID: 23252030 View in Reaxys








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Yield Conditions & References

Example Name 9


Example Name 11


Example Name 4Example Title EXAMPLE 4EXAMPLE 4Preparation of azithromycin monohydrate.5g of crude azithromycin, prepared as described in EP 9803945.4, was dissolved in 37.6 ml of water and 2.4 ml ofhydrochloric acid (6N) at a temperature of from 20.deg.C to 25.deg.C.To this solution was added 10 ml of acetone and 2.8 ml of 20percent (w/v) aqueous sodium hydroxide solution to adjustthe pH to 9.8.After stirring for 4 hours at a temperature of from 20.deg.C to 25.deg.C the suspension was cooled to from 5.deg.C to0.deg.C and stirred for 1 hour at this temperature.The resulting solid was collected by filtration, washed with water (3 times 5 ml of water cooled at 5.deg.C) and dried at35-40.deg.C to give azithromycin monohydrate (4.6g).


O

OH

O

O

HO

O

O

O

N N

O

OH

OH

OH

H

H

HCl 2


Example Name 1Example Title Example 1Example 1To an azithromycin dihydrate solution (5 g, 0.0064 moles) in isopropanol (20 ml), 2.5 ml of a 18percent hydrogen chloridegas solution in dry isopropanol (0.0124 moles of hydrogen chloride gas) were added dropwise under stirring within 5minutes at a temperature of 10-15 .deg.C.The resulting reaction mixture was added dropwise to diisopropyl ether (130 ml) under stirring within 30 minutes.The stirring of the reaction mixture was continued for another hour at room temperature, subsequently the precipitatewas filtered, washed with cold isopropanol (5 ml) and dried for 5 hours in a vacuum dryer at 40 .deg.C. 5.15 g (98.4per-cent) of azithromycin dihydrochloride, m.p. 186-192 .deg.C, were obtained.

Patent; PLIVA, farmaceutska, kemijska, prehrambena, i kozmeticka industrija dionicko drustvo; EP677530;(1995); (A1) EnglishView in Reaxys

Example Name 2Example Title Example 2Example 2To an azithromycin dihydrate solution (5g, 0.0064 moles) in acetone (10 ml), 2.5 ml of a 18percent hydrogen chloridegas solution in dry isopropanol (0.0124 moles of hydrogen chloride gas) were added dropwise under stirring within 5minutes at a temperature of 10-15 .deg.C.Subsequently, while keeping the same temperature, diisopropyl ether (60 ml) was added dropwise into the reactionmixture within 1 hour.







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After stirring for 1 hour at the same temperature, the precipitated salt was filtered off. 5.20 g (98.9percent) of azithro-mycin dihydrochloride were obtained.


Example Name 4Example Title Example 4Example 4According to the process described in Example 1, from azithromycin monohydrate (2g, 0.0026 moles) dissolved inmethanol (8 ml), 1.16 ml of 12.9percent hydrogen chloride gas solution in dry methanol (0.0041 moles of hydrogenchloride gas) and diisopropyl ether (16 ml), 2.10 g (98.5percent) azithromycin dihydrochloride were obtained.


9-deoxo-9a-aza-9a-methyl-9a-homoerythromy‐cin A

O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH


Example Title Preparation of non-crystalline 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A. Method APreparation of non-crystalline 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A. Method A5 g of crystalline azithromycin monohydrate are dissolved in 25 ml of tert-butanol heating at 30.deg. C.This solution is filtered and solidified in a cooling bath.The solvent is sublimed at room temperature and 10-2 mm Hg.The solid obtained is dried (80 mm Hg/40.deg. C.) to yield 5 g of non-crystalline azithromycin.IR (KBr) vmax=3500, 1740, 1470, 1280, 1268, 1257 cm-1 (See FIG. 2) 1H-NMR (CDCl3), 13C-NMR (CDCl3), m/e, TLCand HPLC are identical to those of the previous example percent H2O (K. F.)=3.0percent DSC=See FIG. 3X-RayDiffraction=See FIG. 4


Example Title Preparation of non-crystalline 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A. Method B.Preparation of non-crystalline 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A. Method B.5 g of crystalline azithromycin monohydrate are dissolved in 25 ml of ethanol.The solution is filtered and the solvent evaporated at room temperature and 150 mm Hg.The solid obtained is dried (80 mm Hg/40.deg. C.) to yield 5 g of non-crystalline azithromycin, which analytical data areidentical to those of the previous example.








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OH

O

OH

O

O

OH

O

O

O

N N

O

HO

OH

OH

H 2 O

3

10 10


89 % Example Name 5EXAMPLE 5; 100 gms of Azithromycin Monohydrate Isopropanol Clathrate is suspended in Isopropanol 300 ml. Themixture is heated at 50 to 55.deg. C. temp or dissolves the solid completely. In the reaction mixture water (450 ml) isadded at the period of 15 to 30 minutes and stirred at six hrs at 20 to 30.deg. C. The resulting product is filtered andwashed with (50:50) IPA: water mixture. The product is dried under vacuum (1 mm to 10 mm Hg) at 25-50.deg. C.temp. Yield 89.0 gms (89percent). IPA=3.35percent Water=2.10percent

, Purification / work up

Patent; ALEMBIC LIMITED; US2006/19908; (2006); (A1) EnglishView in Reaxys

OH O

OH

O

O

HO

O

O

O

N N

O

HO

OH

OH

H

H

H 2 O


Example Name 6.B






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Reaxys_NDF_Azithromycin