FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
AMORPHOUS OCTREOTIDE ACETATE AND PROCESS FOR PREPARATION THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai - 400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to amorphous octreotide acetate and process for preparation thereof.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. DESCRIPTION
The present invention relates to amorphous octreotide acetate and process for preparation thereof.
Octreotide is an octapeptide. It is a long-acting octapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin. Octreotide is indicated to reduce blood levels of growth hormone and IGF-I in acromegaly patients. It is also indicated for the symptomatic treatment of patients with metastatic carcinoid tumors and Vasoactive Intestinal Peptide Tumors (VIPomas)

US Patent No 4,395,403 (the '403 Patent) and European Patent No EP029, 579 (the '579 Patent) discloses solution synthesis for the preparation of octreotide.
Several solid phase synthesis procedures have been subsequently described viz. European Patent No EP 953,577 and U.S. Pat. No 5,889,146 and in various research publications. Mergler et al (Proceedings of the 12.sup.th American Peptide Symposium) have used aminomethyl resin and Fmoc-butyl protection scheme for synthesis of octreotide. Alsina et al. Tetrahedron Letters, 38, 883, 1997) have used an active carbonate resin and Boc-Bzl protection scheme,
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necessitating the use of hydrogen fluoride/anisole for final deprotection. Edwards et al (J. Med. Chem., 37, 3749, 1994)) have described another synthesis using Fmoc-butyl protection and HMP resin, and Berta et al (EP 0 953 577) described a synthesis using 2-chlorotrityl-type resin and Fmoc-butyl protection scheme.
The present inventors surprisingly found that amorphous form of octreotide acetate can be prepared by simple techniques from trifluoroacetate salt of H-(D)-Phe1-Cys(Acm)2-Phe3-(D)-Trp4-Lys5-Thr6-Cys(Acm)7-Thr8-OL (i. e. 8P-OL). The amorphous form of octreotide acetate offers several advantages in terms of enhanced solubility, greater stability and ease in incorporation to dosage form.
In one of the aspect of the present invention there is provided amorphous octreotide acetate. The amorphous octreotide acetate of the present invention has characteristic powdered X-Ray Diffraction (XRD) pattern as depicted in Figure 1 of the accompanied drawing. The amorphous octreotide acetate has characteristic FTIR pattern as depicted in Figure 2 of the accompanied drawing.
In another aspect of the present invention there is provided a process for preparation of octreotide acetate, wherein the said process comprises of
a) charging octreotide or salt thereof wherein the salt is other than acetate, over preparative chromatography column,
b) eluting the column with 0.1 to 4% ammonium acetate and 0.1-2% acetic acid,
c) further, eluting the column with a mixture comprising of acetic acid and methanol,
d) concentrating the desired fraction,
e) isolating octreotide acetate from the concentrate of step d).
Powder XRD of the samples were determined by Rigaku X-Ray diffractometer model no. 2200-v Japan.
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FT IR of the samples were determined by Perkin Elmer, Spectrum One FT-IR spectrometer in KBr pallets.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example Preparation of Amorphous Octreotide acetate
Octreotide-trifluoroacetate salt (16gm) charged on preparative HPLC and
removed trifluoroacetatic acid with elution of 3% ammonium acetate. The column
was further eluted with 1% acetic acid to convert octreotide base to octreotide
acetate, which is then eluted from the column using a mixture of methanol and
acetic acid. The desired fraction containing octreotide acetate were concentrated
and concentrated mass was lyophilized to yield titled product.
Yield = 10gm
HPLC purity = 99.16%
ESMS=1019(M+H)
[d]25D= -66.8° (C=1, GLACIAL ACETIC ACID)
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WE CLAIM:
1. Amorphous octreotide acetate.
2. Amorphous octreotide acetate having characteristic powdered X-Ray Diffraction (XRD) pattern as depicted in Figure 1.
3. Amorphous octreotide acetate having characteristic FTIR spectrum as depicted in Figure 2.
4. A process for preparation of octreotide acetate, wherein the said process comprises of

a) charging octreotide or salt thereof wherein the salt is other than acetate, over preparative chromatography column,
b) eluting the column with 0.1 to 4% ammonium acetate and 0.1-2% acetic acid,
c) further, eluting the column with a mixture comprising of acetic acid and methanol,
d) concentrating the desired fraction,
e) isolating octreotide acetate from the concentrate of step d).
5. A process of claim 4 wherein isolation of octreotide acetate further
comprises lyophilization of the concentrate.
Dated this 31st day of August, 2006 For Wockhardt Limited
(Mandar Midgule) Authorized Signatory
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