Teva Pharmaceutical Industries Limited

Teva Pharmaceutical Industreis, Ltd.

Igor Lifshitz

Ilya Avrutov

Edi Schwartz

Basem Masarwa

Elizabeth Lewiner

Judith Aronhime

Ben-Zion Dolitzky

Shlomit Wizel

Revital Lifshitz-Liron

Boaz Gome

Dov Diller

Barnaba Krochmal

Iiya Avrutov

Ramiy Lidor-Hadas

Nissm Sasson

Ronen Borochovitz

Provided is a crystalline (polymorphic) form of fexofenadine hydrochloride, denominated fexofenadine hydrochloride Form XVI.

Polymorphic Form XVI of fexofenadine hydrochloride

The present invention relates to a method of making risedronate sodium substantially free of iron including the steps of refluxing, especially with mechanical agitation, a combination of risedronic acid, a sodium base, especially sodium hydroxide, and an iron-reducing amount of EDTA in a liquid that is water, a lower alkanol, or, especially, a mixture of a lower alkanol and water; and isolating risedronate sodium substantially free of iron from the combination.

Risedronate sodium having a very low content of iron

The present invention relates to processes for preparing protected silylated clarithromycin oxime, preferably 6-O-methyl-2',4&#x2033;-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl)oxime ('S-MOP oxime'), and for converting protected silylated clarithromycin oxime, preferably S-MOP oxime, to clarithromycin. Processes for preparing protected silylated clarithromycin oxime according to the present invention, include reacting a silyl oxime derivative with methylating agent in the presence of at least one solvent and a base, where the solvent comprises methyl tertbutyl ether. Processes for converting protected silylated clarithromycin oxime to clarithromycin according to the present invention, include reacting protected silylated clarithromycin oxime with ethanol and water at an ethanol to water ratio of about 1:1, in the presence of an acid and a deoximating agent and cooling the reaction mixture prior to adding sodium hydroxide, where the process takes place without any additional water addition. Further processes for converting protected silylated clarithromycin oxime to clarithromycin, include heating a mixture of protected silylated clarithromycin oxime, acid, and deoximating agent in an ethanol/water solvent to reflux for more than 4 hours, with a two-fold addition of deoximating agent to produce essentially oxime-free clarithromycin.

Processes for preparing clarithromycin and clarithromycin intermediate, essentially oxime-free clarithromycin, and pharmaceutical composition comprising the same

The present invention relates to processes for converting clarithromycin Form I to clarithromycin Form II, which include slurrying clarithromycin the Form I in water. The present invention also relates to processes for the preparation of clarithromycin Form II by converting erythromycin A to clarithromycin and thereafter converting clarithromycin Form I to clarithromycin Form II by slurrying.

Processes for preparing clarithromycin polymorphs

The present invention relates to processes for preparing protected silylated clarithromycin oxime, preferably 6-O-methyl-2&prime;, 4&Prime;-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl)oxime (&ldquo;S-MOP oxime&rdquo;), and for converting protected silylated clarithromycin oxime, preferably S-MOP oxime, to clarithromycin. Processes for preparing protected silylated clarithromycin oxime according to the present invention, include reacting a silyl oxime derivative with methylating agent in the presence of at least one solvent and a base, where the solvent comprises methyl tertbutyl ether. Processes for converting protected silylated clarithromycin oxime to clarithromycin according to the present invention, include reacting protected silylated clarithromycin oxime with ethanol and water at an ethanol to water ratio of about 1:1, in the presence of an acid and a deoximating agent and cooling the reaction mixture prior to adding sodium hydroxide, where the process takes place without any additional water addition. Further processes for converting protected silylated clarithromycin oxime to clarithromycin, include heating a mixture of protected silylated clarithromycin oxime, acid, and deoximating agent in an ethanol/water solvent to reflux for more than 4 hours, with a two-fold addition of deoximating agent to produce essentially oxime-free clarithromycin.

The present invention relates to processes for converting clarithromycin Form 0 to clarithromycin Form II, which include slurrying clarithromycin the Form 0 in water. The present invention also relates to processes for the preparation of clarithromycin Form II by converting erythromycin A to clarithromycin and thereafter converting clarithromycin Form 0 to clarithromycin Form II by slurrying. The present invention further relates to the novel clarithromycin polymorph Form IV, a process for its preparation, pharmaceutical compositions comprising the compound, and methods of using the compound as a therapeutic agent.

Processes for preparing clarithromycin polymorphs and novel polymorph IV

The present invention provides a process for preparing crystalline lorazepam substantially free of bound solvent from a lorazepam alcohol solvate or hydrate by suspending the lorazepam solvate in an organic medium selected from ethyl acetate, cyclohexane, dichloromethane, toluene and mixtures thereof. This process is useful in producing the anti-anxiety and sedative agent lorazepam in increased yields. A process for converting lorazepam lower alcohol solvates to lorazepam hydrate is also disclosed.

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Petach Tikva, Israel

Igor Lifshitz