The structure of Omeprazole in the solid state: a 13C and 15N NMR/CPMAS study

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Feb 172015

ARKIVOC Volume 2006
Part (v): Commemorative Issue in Honor of
Facilitator: Luba Ignatovich
Scientific Editor: Mikael Begtrup

2. The structure of Omeprazole in the solid state: a 13C and 15N NMR/CPMAS study (EL-1719AP)
Rosa M. Claramunt, Concepción López and José Elguero
Full Text: PDF (193K)
pp. 5 – 11

The structure of Omeprazole in the solid state: a 13C and 15N NMR/CPMAS study

Rosa M. Claramunt,a Concepción López,a and José Elguero b *

a Departamento de Química Orgánica y Bio-Orgánica, Facultad de Ciencias, UNED, Senda del Rey 9, E-28040 Madrid, Spain

b Instituto de Química Médica, CSIC, Juan de la Cierva, 3. E-28006 Madrid, Spain E-mail: iqmbe17@iqm.csic.es

To our friend Professor Edmunds Lukevics on his 70th anniversary

Edmunds Lukevics

Abstract

The 13C and 15N CPMAS spectra of a solid sample of Omeprazole have been recorded and all the signals assigned. The sample consists uniquely of the 6-methoxy tautomer. For analytical purposes, the signals of the other tautomer, the 5-methoxy one, were estimated from the data in solution (Magn. Reson. Chem. 2004, 42, 712).

Keywords: Omeprazole, NMR, 13C, 15N, CPMAS, tautomerism, benzimidazole

see at

http://www.arkat-usa.org/arkivoc-journal/browse-arkivoc/2006/5/graphical-abstracts/

http://www.arkat-usa.org/get-file/22955/

Edmunds LUKEVICS

(14.12.1936 – 21.11.2009)

Professor Edmunds LUKEVICS
Latvian Institute of Organic Synthesis,
Head of the Laboratory of Organometallic ChemistryAizkraukles iela 21,
Riga, LV-1006
Latvia

Born: December 14, 1936, Liepaja, Latvia
Departed: November 21, 2009, Riga, Latvia

Interests:

Organometallic Compounds
Heterocyclic Compounds
Biological Activity of Organic Compounds

Main Research:

Development of methods for the synthesis of organosilicon and -germanium derivatives of furan, thiophene and nitrogen-containing heterocycles ; study of the influence of organosilicon ,-germanium and -tin substituents on the direction of substitution and addition reactions of furan and thiophene derivatives ; study of hydrosilylation and hydrogermylation reactions, synthesis and investigation of properties of penta- and hexacoordinated organosilicon and -germanium derivatives; application of alkenyl silanes and germanes in the synthesis of nitrogen-containing heterocycles; application of phase-transfer catalysis and ultrasonic irradiation in organometallic synthesis; synthesis of biologically active organosilicon and organogermanium compounds and studies of their properties.

Education:

University of Latvia (Faculty of Chemistry), 1958
Dr.chem. (Candidate of Science in former USSR, Ph.D. in Western countries), Latvian Academy of Sciences, Riga, 1966
Dr.habil.chem. (Doctor of Science in former USSR), Latvian Academy of Sciences, Riga, 1973

Experience:

Latvian Institute of Organic Synthesis –

Junior Researcher, 1958-1967
Senior Researcher, 1968-1970
Head, Laboratory of Organometallic Chemistry, 1970 – 2009
Vice-director, 1980-1982
Director, 1982 – 2003

Honours and Awards:

Corresponding Member, Latvian Academy of Sciences , 1982
Full Member, Latvian Academy of Sciences , 1987
Member, New York Academy of Sciences, 1993
The Latvian Academy of Sciences Gustavs Vanags Prize (in Chemistry), 1986
Latvian SSR State Prize, 1974, 1989
S.Hiller Medal (Latvian Institute of Organic Synthesis), 1990
G.Vanags Medal (Riga Technical University), 1991
D.H.Grindel Medal (company ‘Grindex’, Latvia), 1995
L.Liepina Medal (Institute of Inorganic Chemistry, Riga), 1996
The Latvian Academy of Sciences Grand Medal, 1996
Silver Medal of Milan University, 1996
Schmiedebergs Medal (Latvian Pharmacological Society), 1998
The Latvian Academy of Sciences and Company “GRINDEX” Prize, 1999
Paul Walden’s Medal (Riga Technical University), 2000
Latvian Academy of Sciences Presidium Award, 1971, 1973, 1977, 1981, 1982, 1985,1987, 1989, 1992
International Man of the Year (The International Biographic Centre of Cambridge, England), 1992-1993, 1994-1995
Man of the Year (The American Biographical Institute), 1994, 2005
The first-level Badge of Honour of the Order of Three Stars, 1997
Company “Grindex” gold badge of honour, 2001
The Cabinet of Ministers of the Republic of Latvia Prize , 2004
American Medal of Honor (ABI), 2005
Gold Medal for Latvia (ABI), 2006
The Plato Award (IBC), 2006
Man of Achievement (ABI), 2007

Professional Activities:

Member of Presidium and Senate, Latvian Academy of Sciences, 1987-1991
Member of Board, Division of Chemical and Biological Sciences, Latvian Academy of Sciences, 1983-1993
Member, Latvian Academy of Sciences Commission on Terminology, 1987- 1999
Chairman, Habilitation and Promotion Council (Chemistry and Pharmacy), Latvian Institute of Organic Synthesis, 1994 -1999
Member (Chairman,1991-1993, 1997-2002), Latvian Council of Science Expert Committee for Chemistry, 1991 – 2006
Vice-chairman, Habilitation and Promotion Council (Chemistry), University of Latvia, 1998- 2009
Member of Editorial Board for:

Khimiya Geterotsikicheskikh. Soedinenii (Chemistry of Heterocyclic Compounds, Springer), 1980-1985; Editor-in-chief, 1985 – 2009
Proceedings of Latvian Academy of Sciences, 1982-1990
Latvian Journal of Chemistry, 1991 – 2009
Bioorganicheskaya Khimiya, 1989 – 1993
Applied Organometallic Chemistry, 1990 – 2009
Main Group Metal Chemistry, 1992 – 2009
Metal-Based Drugs, 1993 – 2003
Mendeleev Communications, 1994 – 2009
Advances in Heterocyclic Chemistry, 1994 – 2009
Silicon Chemistry, 2001-2007
Arkivoc, 2001 – 2009
Bioinorganic Chemistry and Applications, 2003 – 2006
Heterocyclic Communications, 2005 – 2009
Molecules, 2008 – 2009
Journal of Organic and Pharmaceutical Chemistry (Ukraine), 2009 – 2009

Chairman, Scientific Council “Chemistry and Technology of Sulfur Organic Compounds”, USSR State Committee of Science and Technics, 1982-1987
Chairman, Council “Application of Organometallic Compounds in National Economy”, USSR (Russian) Academy of Sciences, 1984-1992
Member, United Libraries Informative Council, USSR Academy of Sciences, 1985-1990
Member, Scientific Council “Physiologically Active Compounds”, USSR Academy of Sciences, 1986-1992
Member, Scientific and Technical Council, USSR Ministry of Medical and Microbiological Industry, 1987-1990
Member, Soviet National Committee on collecting and estimating information in science and technics “CODATA”, 1987-1990
Member of Council for Coordination of scientific work, Department of Biochemistry, Biophysics and Physiologically Active Compounds, USSR Academy of Sciences, 1988-1991
Member of International Organizing Committees
– International Conference on the Coordination and Organometallic Chemistry of Germanium, Tin and Lead, 1992, 1995, 1998, 2001
– International Symposium on Organosilicon Chemistry, 1993, 1996, 1999, 2002, 2005, 2008.

Memberships:

Member of Organometallic Chemistry Division, Federation of European Chemical Societies, 1995-2005
Member of Organometallic Chemistry Division, European Association for Chemical & Molecular Sciences, 2006
Member, Latvian Chemical Society, 1995
Member, American Chemical Society, 1997
Member, National Geographic Society, 1997
Honorary Member, Pharmacological Society of Latvia, 1998

Lectures

Invited Lectures at Universities

Indian Institute of Science, Bangalore (India), 1989
Indian Institute of Technology, Bombay (India), 1989
University of Dresden (Germany), 1989
Universities of Bordeaux, Tolouse, Montpellier, Marseilles (France), 1990, 1994
University of Lund (Sweden), 1992
University of Alcala de Henares ( Spain), 1993
Tohoku University (Sendai, Japan), 1991, 1992
Tokyo University of Science (Japan), 1997
Kyoto University (Japan), 1997
Universities of Kyoto and Kanagawa, Japan, 2002.

Invited Lectures and Symposium’s Plenary Lectures:

40th Nobel Symposium (Lidingö, Sweden), 1977
VI Symposium on Chemistry of Heterocyclic Compounds (Brno, Czechoslovakia), 1978
7th International Symposium on Organosilicon Chemistry (Kyoto, Japan), 1984
VI FECHEM Conference on Organometallic Chemistry (riga, Latvia), 1985
II Soviet-Indian Symposium on Organometallic Chemistry( Irkutsk, Russia), 1989
17th DDR-Poland Colloquy on Organometallic Chemistry (Holzhau, Germany), 1989
6th International Conference on Organometallic and Coordination Chemistry of Germanium, Tin and Lead (Brussels, Belgium), 1989
Huang Minlon Symposium on Organic Chemistry (Shanghai, China), 1989
International Chemical Conference on Silicon and Tin ( Kuala Lumpur, Malaisia), 1989
9th International Symposium on Organosilicon Chemistry (Edinburgh, UK), 1990
1st Meeting of the European Society of Sonochemistry, Autrans (Grenoble, France), 1990
11th International Symposium on Medicinal Chemistry (Jerusalem, Israel), 1990
S.Hiller Memorial Lectures (Riga, Latvia), 1990
1st Meeting of Japanese Germanium Discussion Group (Tokyo, Japan), 1991
International Conference on Environmental and Biological Aspects of Maingroups Organometals (Padua, Italy), 1991
3rd Swedish-German workshop: Nucleic Acid Synthesis, Structure and Function (Uppsala, Sweden), 1992
2nd ANAIC Conference on Materials Science and Environmental Chemistry of Main Group Elements (Kual Lumpur, Malaysia), 1993
Todai Symposium “Ge-Sn-Pb Tokyo’93”: International Symposium on Organic, Bioorganic and Bioinorganic Chemistry of Compounds of higher row Group 14-elements (Tokyo, Japan), 1993
10th International Symposium on Organosilicon Chemistry (Poznan, Poland), 1993
3rd Meeting of the European Society of Sonochemistry (Figueira da Foz, Portugal), 1993
14th Nordic Meeting of Structural Chemists (Helsinki, Finland), 1993
8th International Conference on the Organometallic Chemistry of Germanium, Tin and Lead (Sendai, Japan), 1995
8th IUPAC Symposium on Organometallic Chemistry Directed Towards Organic Synthesis (Santa Barbara, USA), 1995
8th Symposium Heterocycles in Bioorganic Chemistry (Como, Italy), 1996
9th International Conference on the Coordination and Organometallic Chemistry of Germanium, Tin, and Lead (Melbourne, Australia), 1998
12th International Conference on Organosilicon Chemistry (Sendai, Japan), 1999
International Conference on Organic Synthesis “Balticum Organicum Sinteticum-2000″(Vilnius, Lithuania), 2000
X International Symposium “Jubilee Krka Prizes” (Novo Mesto, Slovenia), 2000

Recent/Representative Publications:

E.Ya. Lukevits, M.G.Voronkov. Organic Insertion Reactions of Group IV Elements, 1966, New York: Consultants Bureau, 413 pp.
S.N.Borisov, M.G.Voronkov, E.Ya.Lukevits. Organosilicon Heteropolymers and Heterocompounds, 1970, NewYork: Plenum Press, 633 pp.
S.N.Borisov, M.G.Voronkov, E.Ya.Lukevits. Organosilicon Derivatives of Phosphorus and Sulfur, 1971, NewYork; London: Plenum Press, 343 pp.
M.G.Voronkov, G.I..Zelchan, E.Ya.Lukevits. Silizium und Leben, 1975, Berlin: Akademie-Verlag, 370 pp.
E.Lukevics, O.Pudova, R.Sturkovich. Molecular Structure of Organosilicon Compounds, 1989, Chichester: Ellis Horwood Ltd., 359 pp.
E.Lukevics, T.Gar, L.Ignatovich, V.Mironov. Biological Activity of Germanium Compounds, 1990, Riga: Zinatne, 191 pp. (in Russian).
E.Lukevics, A.Zablocka. Nucleoside Synthesis: Organosilicon Methods, 1991, Chichester: Ellis Horwood, 496 pp.
E.Lukevics, L.Ignatovich. Biological activity of organogermanium compounds. – In: The Chemistry of Organic Germanium, Tin and Lead Compounds/Ed. Z.Rappoport/, Wiley, Chichester, 2002, vol. 2, pt. 2, pp. 1653-1683.
E.Lukevics, O.Pudova. Biological activity of organogermanium compounds. – In: The Chemistry of Organic Germanium, Tin and Lead Compounds/Ed. Z.Rappoport/, Wiley, Chichester, 2002, vol. 2, pt. 2, pp. 1685-1714.

E.Lukevics, O.Pudova. Silyl imidic esters. – In: Science of Synthesis, Thieme, 2002, vol. 4, pp. 305-315.
E. Lukevics, P. Arsenyan, S. Belyakov, O. Pudova. Synthesis, structure and chemical transformations of ethynylgermatranes – Eur. J. Inorg. Chem., 2003, Iss.17, pp.3139-3143.
R. Abele, E. Abele, M. Fleisher, S. Grinberga, E. Lukevics. Novel fluoride ion mediated synthesis of unsymmetrical siloxanes under phase transfer catalysis conditions. – J. Organomet. Chem., 2003, vol.686, N 1/2, pp.52-57.
E. Lukevics, L. Ignatovich, I.Shestakova. Synthesis, psychotropic and anticancer activity of 2,2-dimethyl-5-[5-trialkylgermyl(silyl)-2’-hetarylidene]-1,3-dioxane-4,6-diones and their analogues. – Appl.Organomet. Chem., 2003, vol. 17, N 12, pp.898-905.
P. Arsenyan, K. Rubina, I. Shestakova, E. Abele, R. Abele, I. Domracheva, A. Nesterova, J. Popelis, E. Lukevics. Synthesis and cytotoxicity of silylalkylthio-substituted N-heterocycles and their hydroselenites. – Appl. Organomet. Chem., 2003, vol. 17, N 11, pp.825-830.
E. Lukevics, L. Ignatovich, T. Shul’ga, S. Belyakov. The crystal structure of 2-benzo[b]thienylgermatrane. – Appl. Organomet. Chem., 2003, vol. 17, N 9, pp.745-746.
K. Rubina, E. Abele, P. Arsenyan, M. Fleisher, J. Popelis, A. Gaukhman, E. Lukevics. The role of palladium catalyst and base in stereoselective tranformations of (E)-2-chlorovinylsulfides. –Tetrahedron, 2003, vol.59, N 38, pp.7603-7607.
I. Iovel, L. Golomba, J. Popelis, S. Grinberga, E. Lukevics Catalytic hydrosilylation of furan, thiophene, and pyridine aldimines. – Chem. Heterocycl. Comp., 2003, vol.39, N 1, pp.49-55.
G. Veinberg, M. Vorona, I. Shestakova, I. Kanepe, E. Lukevics. Design of ß-lactams with mechanism based nonbacterial activities. – Current Medicinal Chemistry, 2003, vol.10, N 17, pp.1741-1757.
E. Lukevics, P. Arsenyan, O. Pudova. Methods for the synthesis of oligothiophenes. – Heterocycles, 2003, vol.60, N 3, pp.663-687.
V.Dirnens, V.Klusa, J.Skuyins, S.Svirskis, S.Germane, A.Kemme, E.Lukevics. Synthesis and pharmacological activity of silyl isoxazolines-2. – Silicon Chemistry, 2003 (publ. 2004), vol. 2, N 1/2, pp. 11-25.
I.Iovel, L.Golomba, M.Fleischer, J.Popelis, S.Grinberga, E.Lukevics. Hydrosilylation of (hetero)aromatic aldimines in the presence of Pd(I) complex. – Chem.Heterocycl. Comp., 2004, vol. 40, N 6, pp. 701-714.
P.Arsenyan, O.Pudova, J.Popelis, E.Lukevics. Novel radial oligothienylsilanes. – Tetrahedron Lett., 2004, vol. 45, N 15, pp. 3109-3111.
E.Lukevics, L.Ignatovich, S.Belyakov. Crystallographic report: 2-furfurylgermatrane. – Appl. Organomet. Chem., 2004, vol. 18, N 4, p. 203.
G. Veinberg, I. Shestakova, M. Vorona, I. Kanepe, E. Lukevics. Synthesis of antitumor 6-alkylidenepenicillanate sulfones and related 3-alkylidene-2-azetidinones. – Bioorg. Med. Chem. Letters, 2004, vol. 14, No 1, 147-150.
E.Lukevics, L.Ignatovich, T.Shulga, S.Belyakov. 1-[4-(2-Thienyl)phenyl]germatrane. – Appl. Organomet. Chem., 2005, vol. 19, N 1, pp. 167-168.
E.Lukevics, L.Ignatovich. Biological activity of organosilicon compounds. – In: Metallotherapeutic Drugs and Metal-Based Diagnostic Agents. The Use of Metals in Medicine / Eds. M.Gielen, E.R.T.Tiekink/, 2005, J.Wiley & Sons, Ltd. Chichester, pp. 83-107.
E.Lukevics, L.Ignatovich. Biological activity of organogermanium compounds. – In: Metallotherapeutic Drugs and Metal-Based Diagnostic Agents. The Use of Metals in Medicine / Eds. M.Gielen, E.R.T.Tiekink/, 2005, J.Wiley & Sons, Ltd. Chichester, pp. 279-295.
Yu.Melnik, M.Vorona, G.Veinberg, J.Popelis, L.Ignatovich, E.Lukevics. Synthesis and stereoisomerization of 2-(1-alkoxyimino-2,2,2-trifluoroethyl)-5-trimethylsilylfurans. – Chem. Heterocycl. Comp., 2005, vol. 41, N 6, pp. 718-721.
L.Ignatovich, J.Popelis, E.Lukevics. Synthesis and NMR spectra of diaryl- and dihetarylsilacycloalkanes. – In: Organosilicon Chemistry VI / Eds. N.Auner and J.Weis/, Wiley-VCH Weinheim, 2005, vol. 1, pp. 559-562.
L.Ignatovich, D.Zarina, I.Shestakova, S.Germane, E.Lukevics. Synthesis and bological activity of silicon derivatives of 2-trifluoroacetylfuran and their oximes. – In: Organosilicon Chemistry VI / Eds. N.Auner and J.Weis/, Wiley-VCH Weinheim, 2005, vol. 1, pp. 563-568.
E.Lukevics, L.Ignatovich, I.Sleiksha, I.Shestakova, I.Domrachova, J.Popelis. Synthesis and cytotoxic activity of silacycloalkylsubstituted heterocyclic aldehydes. – Appl. Organomet. Chem., 2005, vol. 19, N 10, pp. 1109-1113.
S.Belyakov, E.Alksnis, V.Muravenko, I.Turovskis, J.Popelis, E.Lukevics. Crystal structure and conformation of 8-(2-hydroxyethylamino)- and 8-(pyrrolidin-1-yl)adenosines. – Nucleosides, Nucleotides & Nucleic Acid, 2005, vol. 24, N 8, pp. 1199-1208.
A. Zablotskaya, I.Segal, S.Belyakov, E.Lukevics. Silyl modification of biologically active compounds. 11. Synthesis, physico-chemical and biological evaluation of N-(trialkoxysilylalkyl)tetrahydro(iso,silaiso)quinoline derivatives. Appl. Organomet. Chem. 2006, vol.20, N 2, 149-159.
A.Zablotskaya, I.Segal, J.Popelis, E.Lukevics, S.Baluja, I.Shestakova, I.Domracheva. Silyl modification of biologically active compounds. 12. Silyl group as true incentive to antitumour and antibacterial action of choline and colamine analogues. – Appl. Organomet. Chem. 2006, vol. 20, N 11, 721-728.
E.Lukevics, L.Ignatovich, I.Sleiksha, V.Muravenko, I.Shestakova, S.Belyakov, J.Popelis. Synthesis, structure and cytotoxic activity of 2-acetyl-5-trimethylsilylthiophene(furan) and their oximes. – Appl. Organomet. Chem. 2006, vol 20, N 7, 454-458.
L.Ignatovich, V.Muravenko, S.Grinberga, E.Lukevics. Novel reactions to form an Si-O-Ge group. – Chem.Heterocycl. Comp., 2006, vol. 42, N 2, 268-271.
E.Lukevics, I.Shestakova, I.Domrachova, A.Nesterova, Y.Ashaks, D.Zaruma. Synthesis of complex compounds of methyl derivatives of 8-quinolineselenol with metals and their cytotoxic activity. – Chem.Heterocycl. Comp., 2006, vol. 42, N 1, 53-59.
E.Lukevics, L.Ignatovich, I.Sleiksha, V.Romanov, S.Grinberga, J.Popelis, I.Shestakova. A New method for the synthesis of silicon- and germanium-containing 2-acetylfurans and 2-acetylthiophenes. –Chem.Heterocycl. Comp., 2007, vol. 43, N 2, 143-150.
V.Dirnens, I.Skrastina, J.Popelis, E.Lukevics. Synthesis of isoxazolinylxanthines. – Chem.Heterocycl. Comp., 2007, vol. 43, N 2, 193-196.
E.Lukevics, L.Ignatovich, S.Belyakov. Disordering in the crystal structure of thienylgermatranes. – Chem.Heterocycl. Comp., 2007, vol. 43, N 2, 243-249.
E.Lukevics, I.Shestakova, I.Domrachova, E. Yashchenko, D.Zaruma. Y.Ashaks. Cytotoxic di(8-quinolyl)disulfides. – Chem.Heterocycl. Comp., 2007, vol. 43, N 5, 629-633.
V.M.Vorona, I.Potorocina, G.Veinberg, I.Shestakova, I.Kanepe, M.Petrova, E. Liepinsh, E.Lukevics. Synthesis and structural modification of tert-butyl ester of 7a-chloro-2-(N,N-dimethylaminomethylene)-3-methyl-1,1-dioxoceph-3-em carboxylic acid.- Chem.Heterocycl. Comp., 2007, vol. 43, N 5, 646-652.
A.Zablotskaya, I.Segal, E.Lukevics, S.Belyakov, H.Spies. Tetrahydroquinoline and tetrahydroisoquinoline mixed ligand rhenium complexes with the SNS/S donor atom set.- Appl.Organomet.Chem.,2007, vol.21, N 4, 288-293.
A.Zablotskaya, I.Segal, M. Maiorov, D. Zablotsky, A. Mishnev E.Lukevics, I.Shestakova, I. Domracheva. Synthesis and characterization of nanoparticles with an iron oxide magnetic core and a biologically active trialkylsilylated aliphatic alkanolamine shell. J. Magn. Magn. Mater. 2007, 311, pp. 135-139.
Zablotskaya A., Segal I., Lukevics E., Maiorov M., Zablotsky D., Blums E., Shestakova I., Domracheva I. Synyhesis, physico-chemical and biological study of trialkylsiloxyalkylamine coated iron oxide/oleic acid magnetic nanoparticles for the treatment of cancer. – Appl. Organomet. Chem. 2008, vol. 22, pp. 82-88.
E.Lukevics, E.Abele. Four-membered rings with three heteroatoms not including oxygen, sulfur or nitrogen atom. – In: Comprehensive Heterocyclic Chemistry III., 2008, 2. Four-membered heterocycles together with all fused systems containing a four-membered heterocyclic ring (Exec. Ed. A. Katritzky, FRS: Eds Ch.A. Ramsden, E.V.Scriven, R.J.Taylor), pp. 973-989.
Soualami S., Ignatovich L., Lukevics E.,Ourari A., Jouikov V. Electrochemical oxidation of benzylgermatranes. – J. Organomet. Chem., 2008, vol.693 (7), pp. 1346-1352.
Lukevics E., Ignatovich L., Shul’ga T., Belyakov S. Synthesis and crystal structure of 1-(4-fluorophenyl)- and 1-(4-dimethylamino)phenylgermatranes. – Chem. Heterocycl.Comp. (Engl.Ed.), 2008, vol. 44 (5), pp. 615-620.
Abele E., Lukevics E. Synthesis of Heterocycles from Oximes. – In: The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids. (Eds. Z.Rapoport, J.F.Liebmann ), J.Wiley, Chichester, 2009, Part I, pp. 233-302.
Erchak N., Belyakov S., Kalvinsh I., Pypowski K., Valbahs E., Lukevics E. Two polymorphic modifications of 1-(N-morpholiniomethyl)spirobi(3-oxo-2,5-dioxa-1-silacyclopentan)ate hydrate. –Chem.Heterocycl. Comp.(Engl. Ed.), 2009, vol. 45, N 9, pp.1137-1143..
Zablotskaya A.,Segal I., Lukevics E., Maiorov M., Zablotsky D., Blums E., Shestakova I., Domracheva I. Water-soluble magnetic nanoparticleswith biologically active stabilizers. – J.Magn.Mater.,2009, 321, pp. 1428-1432.
Ignatovich L., Muravenko V., Shestakova I., Domracheva I, Popelis J., Lukevics E. Synthesis and Cytotoxic activity of new 2-[(3-aminopropyl)- dimethylsilyl]-5-triethylsilylfurans. – Appl. Organomet. Chem. 2009, DOI 10.1002, aoc, 1538.
Vorona M., Veinberg G.,Liepinsh E., Kazoka H., Andrejeva G., Lukevics E. Enzymatic synthesis of amoxycilloic acids. – Chem.Heterocycl. Comp.(Engl. Ed.), 2009, vol. 45, N 6, pp.782-754.
Zablotskaya A.,Segal I., Lukevics E. Iron oxide-based magnetic nanostructures bearing cytotoxic organosilicon molecules for drug delivery and therapy. – Appl. Organomet. Chem. 2010, vol. 24, N 3, pp. 150-157.
Ignatovich L., Muravenko V., Shestakova I., Domracheva I, Popelis J., Lukevics E. Synthesis and Cytotoxic activity of new 2-[(3-aminopropyl)- dimethylsilyl]-5-triethylsilylfurans. – Appl. Organomet. Chem. 2010, vol. 24, N 3, pp. 158-161.
Segal I., Zablotskaya A.,Lukevics E., Maiorov M., Zablotsky D., Blums E., Mishnew A., Georgieva R., Shestakova I., Gulbe A. Preparation and cytotoxic properties of goethite-based nanoparticles covered with decyldimethyl(dimethylaminoethoxy)silane metoxyde. – Appl. Organomet. Chem. 2010, vol. 24, N 3, pp. 193-197.
Ignatovich L., Muravenko V., RomanovsV, Sleiksha I., Shestakova I., Domracheva I, Belyakov S., Popelis J., Lukevics E. Synthesis, structure and cytotoxic activity of new 1-[5-organylsilyl(germyl)-2-furyl(thienyl)]nitroethenes. – Appl. Organomet. Chem. 2010, vol. 24, N 12, pp. 858-864.
Lukevics E., Abele E., Ignatovich L. Biologically Active Silacyclanes. – Adv. Heterocycl. Chem., 2010, vol. 99, pp. 107-141.
Abele E., Lukevics E. Synthesis, structure and reactions of organometallic derivatives of oximes. – In: The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids. Eds. by Zvi Rapoport, J.F.Liebman. 2011, Vol.2, Part 1 (Chapter 4), pp. 145-203.
Katkevics M., Kukosha T., Lukevics E. Heterocycles from hydroxylamines and hydroxamic acids. – In: The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids. Eds. by Zvi Rapoport, J.F.Liebman. 2011, Vol.2, Part 1 (Chapter 5), pp. 205-293.

Research Projects:

E.Lukevics (Head of Project). Silylheterocycles in Organic Chemistry. Latvian Council of Science (1993-1995).
E.Lukevics (Head of Project). Bifunctional Organosilicon Compounds. Latvian Council of Science (1993-1995).
E.Lukevics (Head of Project). Synthesis of Heterocyclic Organosilicon and Organogermanium Compounds, Investigation of their Physical and Chemical Properties. Latvian Council of Science (1997-2000 ).
E.Lukevics (Head of Project). Asymmetric and Catalytic Synthesis of Heteroaromatic Compounds. Latvian Council of Science (1997-2000 ).
E.Lukevics (Head of Program). The Development of Modern Methods of Organic Chemistry Directed towards the Development of Pharmaceutical Industry in Latvia. Latvian Council of Science (1997-2000 ).
E.Lukevics (Head of Project). Experimental and Theoretical Aspects of the Catalytical Synthesis of Heteroaromatic Compounds. Latvian Council of Science (2001 –2004 ).
E.Lukevics (Head of Project). Comparative Study of the Structure and Biological Activity of Organosilicon and Organogermanium Compounds. Latvian Council of Science (2001 – 2004).
E.Lukevics (Head of Project). Heterocyclic Derivatives of Tetra- and Hypercoordinated Germanium and Silicon. Latvian Council of Science (2005 -).
E.Lukevics ( Programme Director). Development of Organic Synthesis Methods for Obtaining of Biologically Active Compounds. Latvian Council of Science (2002 -2005 ).
E.Lukevics ( Programme Director). Development of Heteroatom Chemistry for Preparation of Biologically Active Compounds. Latvian Council of Science (2006 – 2009 ).
E.Lukevics (Head of Project). Carbofunctional Silylheterocycles. Latvian Council of Science (2009 ).

Hobbies:

Opera, Basketball, Mountains.

Edmunds LUKEVICS

Edmunds LUKEVICS
Head of Laboratory of Organometallic Chemistry

Latvian Institute of Organic Synthesis

Aizkraukles iela 21,
Riga, LV-1006
http://www.lza.lv/scientists/lukevics.htm

Born: December 14, 1936, Liepaja, Latvia
Departed: November 21, 2009, Riga, Latvia

Interests in inventing:

Development of medicament synthesis and technology
Development of the synthesis and technology of agricultural chemicals

Main invention:

In the sphere of medicament synthesis:

Acylete derivatives of aminobenzylpenicillin with antimicrobe activity.
Co-authors: G.Veinbergs, G.Kvitsors a.o.
Authors’ certificate of USSR Nr.1829360, 1992
Substituted 3-hydrazinopropionates and their pharmaceutically available salts with antiarythmic activity.
Co-authors: G.Bremanis, I. Kalvins, I.Ancena a.o.
Authors’ certificate of USSR Nr.1247012, 1986.
Patent of USA Nr. 4633014
Patent of England Nr. 2144121
Patent of France Nr. 2549050
Patent of Italy Nr.1175577

In the sphere of the synthesis of agricultural chemicals:

2,2 –dimethyl-6-alkyl–1,3-dioxa-6-aza-2-silacyclooctanes with antiinsect activity.
Co-authors: V.Markina, N.Smirnova a.o.
Authors’ certificate of USSR Nr.687855, 1978.
Lucerne productivity stimulator.
Co-authors: L.Sermans, V.Janisevska, G.Zelcans a.o.
Authors’ certificate of USSR Nr. 1161056, 1985

Selection of patent documents:

Totally: 104 authors’ certificates of USSR, 11 patents of Latvia, 3 patents of Germany, 3 patents of Canada, 3 patents of France, 3 patents of Italy, 1 patent of Japan, 1 patent of Switzerland, 4 patents of Great Britain, 5 patents of USA.

Patents of Latvia:

E.Lukevics, D.Feldmane, H.Kazoka, I.Turovskis. Method for obtaining metoxi-alpha-methylbenzyl alcohol. Patent of Latvia Nr. 11864, C 07 C 29/58, 1997;
E.Lukevics, V.Slavinska, Dz.Sile, M.Katkevics, E.Korcagova. Method for obtaining 2-oxo-4-phenylbutane acid ethylester. Patent of Latvia Nr. 11891, C 07 C 69/716, 1998;
E.Lukevics, V.Slavinska, Dz.Sile, M.Katkevics, E.Korcagova, V.Belikovs. Method for obtaining 2-oxo-4-phenylbutane acid ethylester. Patent of Latvia Nr. 11892, C 07 C 69/716, 1998;
E.Lukevics, I.Kalvins, A.Birmans. Cardioprotector “Mildronate”. Patent of Latvia Nr. 5402, A 61 K 31/205, 1994;
E.Lukevics, G.Veinbergs, I.Sestakova, I.Kalvins. Cephalosporin derivatives with citostatic activity. Patent of Latvia Nr. 11953, C 07 D 501/02, 1998.

Riga latvia

The building of the Brotherhood of Blackheads is one of the most iconic buildings of Old Riga (Vecrīga)

RIGA

Cook in traditional latvian dress serving local food for tourists Riga Latvia

Points of interest

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APHRODIASIC CHEMISTRY

drugs Comments Off

Feb 132015

09306-scitech2-aphrodisiacs

SEE……….http://cen.acs.org/articles/93/i6/Periodic-Graphics-Aphrodisiacs.html

Large-Scale Continuous Flow Transformation of Oximes into Fused-Bicyclic Isoxazolidines: An Example of Process Intensification

Uncategorized Comments Off

Feb 122015

Abstract Image

Here, we report a continuous flow protocol for the [3 + 2] cycloaddition of nitrones, in situ generated from oximes, into bicyclic isoxazolidines. This thermal process required very high temperatures to be efficient that were not easily reached in conventional reactors. A couple of examples are presented and in both the flow process showed a greater performance than the batch mode. The process intensification study allowed the generation of 120 g/h of a key pharmaceutical intermediate.

Large-Scale Continuous Flow Transformation of Oximes into Fused-Bicyclic Isoxazolidines: An Example of Process Intensification

see

http://pubs.acs.org/doi/abs/10.1021/op500350y

Juan A. Rincón *†, Carlos Mateos †, Pablo García-Losada †, and Dustin J. Mergott ‡

† Centro de Investigación Lilly S.A., Avda. de la Industria 30, Alcobendas-Madrid 28108, Spain

‡ Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285,United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/op500350y

Publication Date (Web): January 28, 2015

*E-mail: rinconja@lilly.com.

A Green and Sustainable Approach: Celebrating the 30th Anniversary of the Asymmetric l-Menthol Process

MANUFACTURING, SYNTHESIS, Uncategorized Comments Off

Feb 052015

A Green and Sustainable Approach: Celebrating the 30th Anniversary of the Asymmetric l-Menthol Process

Takasago has been devoted to producing l-menthol since 1954, and our long history of manufacturing this important aroma chemical is reviewed here. The current asymmetric catalytic process had its 30th anniversary in 2013. Our l-menthol process is considered carbon-neutral, and, therefore, ‘green’ and sustainable. It uses renewable myrcene obtained from gum rosin as a starting material. In addition, the Rh-BINAP (=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) catalytic system is highly efficient. This pathway not only leads l-menthol, but a variety of 100% biobased aroma chemical products as well. By measuring the ¹⁴C levels in a material, one can determine the percentage of carbon that is biobased. This biobased assay, described as the ratio plant-derived C/fossil-derived C, can clarify how renewable a product really is. This will be highlighted for several of Takasago’s key aroma chemicals.

A Green and Sustainable Approach: Celebrating the 30th Anniversary of the Asymmetric l-Menthol Process

Makoto Emura^* and
Hiroyuki Matsuda

Article first published online: 18 NOV 2014

DOI: 10.1002/cbdv.201400063

Issue

Chemistry & Biodiversity

Volume 11, Issue 11, pages 1688–1699, November 2014

http://onlinelibrary.wiley.com/doi/10.1002/cbdv.201400063/abstract

Production

As with many widely used natural products, the demand for menthol greatly exceeds the supply from natural sources. In the case of menthol it is also interesting to note that comparative analysis of the total life-cycle costs from a sustainability perspective, has shown that production from natural sources actually results in consumption of more fossil fuel, produces more carbon dioxide effluent and has more environmental impact than either of the main synthetic production routes.^[7]

Menthol is manufactured as a single enantiomer (94% ee) on the scale of 3,000 tons per year by Takasago International Corporation.^[8] The process involves an asymmetric synthesis developed by a team led by Ryōji Noyori, who won the 2001 Nobel Prize for Chemistry in recognition of his work on this process:

Menthol synthesis.png

The process begins by forming an allylic amine from myrcene, which undergoes asymmetric isomerisation in the presence of a BINAP rhodium complex to give (after hydrolysis) enantiomerically pure R–citronellal. This is cyclised by a carbonyl-ene-reaction initiated by zinc bromide to isopulegol, which is then hydrogenated to give pure (1R,2S,5R)-menthol.

Another commercial process is the Haarmann-Reimer process. ^[9]^[10] This process starts from m-cresol which is alkylated with propene to thymol. This compound is hydrogenatedin the next step. Racemic menthol is isolated by fractional distillation. The enantiomers are separated by chiral resolution in reaction with methyl benzoate, selective crystallisation followed by hydrolysis.

Racemic menthol can also be formed by hydrogenation of pulegone. In both cases with further processing (crystallizative entrainment resolution of the menthyl benzoate conglomerate) it is possible to concentrate the L enantiomer, however this tends to be less efficient, although the higher processing costs may be offset by lower raw material costs. A further advantage of this process is that d-menthol becomes inexpensively available for use as a chiral auxiliary, along with the more usual l-antipode.^[7]

References

R. Eccles (1994). “Menthol and Related Cooling Compounds”. J. Pharm. Pharmacol. 46 (8): 618–630. PMID 7529306.
Galeottia, N., Mannellia, L. D. C., Mazzantib, G., Bartolinia, A., Ghelardini, C.; Di Cesare Mannelli; Mazzanti; Bartolini; Ghelardini (2002). “Menthol: a natural analgesic compound”.Neuroscience Letters 322 (3): 145–148. doi:10.1016/S0304-3940(01)02527-7. PMID 11897159.
G. Haeseler, D. Maue, J. Grosskreutz, J. Bufler, B. Nentwig, S. Piepenbrock, R. Dengler and M. Leuwer. (2002). “Voltage-dependent block of neuronal and skeletal muscle sodium channels by thymol and menthol”. European Journal of Anaesthesiology 19 (8): 571–579. doi:10.1017/S0265021502000923.
Brain KR, Green DM, Dykes PJ, Marks R, Bola TS; Green; Dykes; Marks; Bola (2006). “The role of menthol in skin penetration from topical formulations of ibuprofen 5% in vivo”. Skin Pharmacol Physiol 19 (1): 17–21. doi:10.1159/000089139. PMID 16247245.
PDR for Herbal Medicines (4th ed.). Thomson Healthcare. p. 640. ISBN 978-1-56363-678-3.
Croteau, R. B.; Davis, E.M.; Ringer, K. L; Wildung, M. R. (December 2005). “(−)-Menthol biosynthesis and molecular genetics”. Naturwissenschaften 92 (12): 562–77.Bibcode:2005NW…..92..562C. doi:10.1007/s00114-005-0055-0. PMID 16292524.
Charles Sell (ed.). The Chemistry of Fragrances: From Perfumer to Consumer. ISBN 978-085404-824-3.
Japan: Takasago to Expand L-Menthol Production in Iwata Plant
After the company Haarmann & Reimer , now part of Symrise
Schäfer, Bernd (2013). “Menthol”. Chemie in unserer Zeit 47 (3): 174. doi:10.1002/ciuz.201300599.

What is 35 U.S. Code § 112 – Specification, ………..it is so easy to understand, try

PATENTS, regulatory Comments Off

Feb 032015

U.S. Code› Title 35 › Part II › Chapter 11 › § 112………more explanation see below

Law is easy, …. learn with me and explained by cornell

I picked this up from site………..http://www.law.cornell.edu/uscode/text

Cock can teach you

thanks to cornell

Cornell law school

http://www.law.cornell.edu/uscode/text

U.S. Code: Table of Contents U.S. Code›

U.S. Code: Title 35 – PATENTS Title 35 ›

35 U.S. Code Part II – PATENTABILITY OF INVENTIONS AND GRANT OF PATENTS Part II ›

35 U.S. Code Chapter 11 – APPLICATION FOR PATENT Chapter 11 ›

§ 112. specification explained in this article

http://www.uspto.gov/web/offices/pac/mpep/mpep-9015-appx-l.html

(a) In General.— The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.

(b) Conclusion.— The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.

(c) Form.— A claim may be written in independent or, if the nature of the case admits, in dependent or multiple dependent form.

(d) Reference in Dependent Forms.— Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.

(e) Reference in Multiple Dependent Form.— A claim in multiple dependent form shall contain a reference, in the alternative only, to more than one claim previously set forth and then specify a further limitation of the subject matter claimed. A multiple dependent claim shall not serve as a basis for any other multiple dependent claim. A multiple dependent claim shall be construed to incorporate by reference all the limitations of the particular claim in relation to which it is being considered.

(f) Element in Claim for a Combination.— An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.

SO EASY TO UNDERSTAND 35 U.S.C. § 112

35 U.S.C. 112 Specification.

[Editor Note: Applicable to any patent application filed on or after September 16, 2012. See 35 U.S.C. 112 (pre-AIA)for the law otherwise applicable.]

(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
(c) FORM.—A claim may be written in independent or, if the nature of the case admits, in dependent or multiple dependent form.
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
(e) REFERENCE IN MULTIPLE DEPENDENT FORM.—A claim in multiple dependent form shall contain a reference, in the alternative only, to more than one claim previously set forth and then specify a further limitation of the subject matter claimed. A multiple dependent claim shall not serve as a basis for any other multiple dependent claim. A multiple dependent claim shall be construed to incorporate by reference all the limitations of the particular claim in relation to which it is being considered.
(f) ELEMENT IN CLAIM FOR A COMBINATION.—An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.

(Amended July 24, 1965, Public Law 89-83, sec. 9, 79 Stat. 261; Nov. 14, 1975, Public Law 94-131, sec. 7, 89 Stat. 691; amended Sept. 16, 2011, Public Law 112-29, sec. 4(c), 125 Stat. 284, effective Sept. 16, 2012.)

35 U.S.C. 112 (pre-AIA) Specification.

[Editor Note: Not applicable to any patent application filed on or after September 16, 2012. See 35 U.S.C. 112 for the law otherwise applicable.]

The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.

The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.

A claim may be written in independent or, if the nature of the case admits, in dependent or multiple dependent form.

Subject to the following paragraph, a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.

A claim in multiple dependent form shall contain a reference, in the alternative only, to more than one claim previously set forth and then specify a further limitation of the subject matter claimed. A multiple dependent claim shall not serve as a basis for any other multiple dependent claim. A multiple dependent claim shall be construed to incorporate by reference all the limitations of the particular claim in relation to which it is being considered.

An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.

(Amended July 24, 1965, Public Law 89-83, sec. 9, 79 Stat. 261; Nov. 14, 1975, Public Law 94-131, sec. 7, 89 Stat. 691.)

SO EASY TO UNDERSTAND 35 U.S.C. § 112

Cornell law school

Cornell seal beneath the tower of Myron Taylor Hall

Interior of Cornell Law School quad

View of Cornell Law School from Central Avenue

Banner outside the law school’sJane M.G. Foster wing

The Cornell Law Library is one of 12 national depositories for print records of briefs filed with the U.S. Supreme Court.

Entrance to Myron Taylor Hall, Cornell Law’s principal building for instruction

Cornell Law School is the law school of Cornell University, a private Ivy League university located in Ithaca, New York. It is one of the five Ivy League law schools and offers three law degree programs (JD, LL.M., and J.S.D.) along with several dual-degree programs in conjunction with other professional schools at the university.

Ithaca
City
From top left: Ithaca during winter, Ithaca during autumn, Cornell University, Ithaca Commons (downtown), Hemlock Gorge in Ithaca, Ithaca Falls
Ithaca
Coordinates: 42°26′36″N 76°30′0″W Coordinates: 42°26′36″N 76°30′0″W
Country	United States
US state	New York
County	Tompkins

Tompkins County, New York

Seal

Location in the state of New York

New York’s location in the U.S.

LEARN A CASE STUDY WITH DR ANTHONY, SO EASY TO UNDERSTAND 35 U.S.C. § 112

case study on this

The Attack of 35 U.S.C. § 112

http://www.google.com/patents/US8598219

September 2, 2014, Accord Healthcare, Inc. (“Accord”) filed what appears to be the second-ever Post-Grant Review (“PGR”) (see Petition). This PGR was for U.S. Patent No. 8,598,219 (“the ‘219 Patent”), which is jointly assigned to Helsinn Healthcare S.A. and Roche Palo Alto, LLC (collectively “Helsinn”).

Helsinn Healthcare Sa, Roche Palo Alto Llc

As a reminder, PGRs are the third type of post-issuance review procedures established by the America Invents Act (“AIA”) — the other two being Inter Partes Review and Covered Business Method Patent Review (IPR and CBM, for short). However, the reason that only one other PGR has been filed to date is because this type of proceeding only applies to patents that were examined pursuant to the new First Inventor to File scheme established by the AIA.

And because such applications could only be filed on or after March 16, 2013, there are only a limited number of such patents that are presently eligible for PGR. One of the other significant differences between IPRs and PGRs is that the latter is not limited to certain types of prior art validity attacks (such as 102 or 103), but instead any type of validity challenge available in District Court is essentially available in front of the Patent Trial and Appeals Board (“PTAB”).

This includes attacks under 35 U.S.C. § 112, such as allegations of a lack of enablement, a lack of written description, and a failure to distinctly claim the invention. Accord took full advantage of this in its petition for PGR2014-00010, in which Accord alleged that Helsinn’s patent related to liquid pharmaceutical formulations of palonosetron should not have been issued by the Patent Office.

Accord Healthcare

The ‘219 patent had been asserted in several Hatch-Waxman litigations involving ALOXI®, which is a palonosetron formulation indicated to help prevent nausea and vomiting following chemotherapy. Palonosetron hydrochloride, the active pharmaceutical ingredient, has the following structural formula:

The ‘219 patent is a member of a family of patents directed to formulations of palonosetron hydrochloride. Importantly, this patent was filed as a continuation-in-part application on May 23, 2013, with a letter that asserted that claim 9 only had support because of a newly added example, and therefore was subject to the AIA. Only claims 1-5 and 8 of the ‘219 patent are the subject of this petition, with claim 1 reading:

1. A pharmaceutical single-use, unit-dose formulation for intravenous administration to a human to reduce the likelihood of cancer chemotherapy-induced nausea and vomiting, comprising a 5 mL sterile aqueous isotonic solution, said solution comprising:
palonosetron hydrochloride in an amount of 0.25 mg based on the weight of its free base;
from 0.005 mg/mL to 1.0 mg/mL EDTA;
and from 10 mg/mL to 80 mg/mL mannitol,
wherein said formulation is stable at 24 months when stored at room temperature.

Claim 8 is the only other challenged independent claim, and it reads identically, except for a stability limitation of 18 months when stored at room temperature. This patent issued on December 3, 2013, and the PGR petition was filed within the requisite nine months.

CLAIMS(8)………..http://www.google.com/patents/US8598219

What is claimed is:

palonosetron hydrochloride in an amount of 0.25 mg based on the weight of its free base;

from 0.005 mg/mL to 1.0 mg/mL EDTA; and

from 10 mg/mL to 80 mg/mL mannitol,

wherein said formulation is stable at 24 months when stored at room temperature.

2. The pharmaceutical formulation of claim 1, wherein said EDTA is in an amount of 0.5 mg/mL.

3. The pharmaceutical formulation of claim 1, wherein said mannitol is in an amount of 41.5 mg/mL.

4. The pharmaceutical formulation of claim 1, wherein said solution further comprises a citrate buffer.

5. The pharmaceutical formulation of claim 4, wherein said citrate buffer is at a concentration of 20 millimolar.

6. The pharmaceutical formulation of claim 1, wherein said solution is buffered at a pH of 5.0 ±0.5.

7. The pharmaceutical formulation of claim 1, wherein said EDTA is in an amount of 0.5 mg/mL, wherein said mannitol is in an amount of 41.5 mg/mL, wherein said solution further comprises a citrate buffer at a concentration of 20 millimolar, and wherein said solution is buffered at a pH of 5.0 ±0.5.

8. A pharmaceutical single-use, unit-dose formulation for intravenous administration to a human to reduce the likelihood of cancer chemotherapy-induced nausea and vomiting, comprising a 5 mL sterile aqueous isotonic solution, said solution comprising:

palonosetron hydrochloride in an amount of 0.25 mg based on the weight of its free base;

from 0.005 mg/mL to 1.0 mg/mL EDTA; and

from 10 mg/mL to 80 mg/mL mannitol, wherein said formulation is stable at 18 months when stored at room temperature.

SO EASY TO UNDERSTAND 35 U.S.C. § 112

The petition pointed out that during the prosecution of the ‘219 patent and its family, the Patent Office had rejected the claimed formulations as obvious. In response, the applicants submitted a declaration from inventor Daniele Bonadeo (“the Bonadeo declaration”) and argued that one of skill in the art would not have combined the features of the invention as a matter of routine optimization. Instead of routine, the applicants continued, the claimed formulations were obtained after a sequence of experiments, each of which built upon the others like building blocks.

If the experimental sequence had varied, the applicants alleged that they would have obtained a different formulation. The Bonadeo declaration explained that the first two parameters studied were palonosetron concentration and pH. None of the studies described in this declaration, however, occurred at a pH other than 5.0, which makes sense because palonosetron was described as extremely stable at this pH.

Considering that the ‘219 patent ultimately issued, the applicants were apparently successful in overcoming these obviousness rejections. In other words, the applicants convinced the examiner that a person of ordinary skill in the art would not have found it obvious to combine the teachings in the prior art to derived the claimed inventions.

The positions taken by the applicant, however, were utilized by the petitioner, Accord, to allege that a person of ordinary skill in the art would not have, for example, found the specification enabling. This highlights the problem that PGRs pose for patent applicants. Before such procedure, arguments could be made without much fear that they would be coopted by the Office for making alternative rejections. And, if the Office did, there would still an opportunity to provide a response or amend the claims. Even if such arguments were made in district court litigation, the patent would at least enjoy a presumption of validity.

Now, all applicants must take extreme caution in making any arguments, because anything said can (and probably will) be used against them at the PTAB.

What follows is an identification of the 35 U.S.C. § 112 arguments made by Accord. Considering that the patent owner has not yet filed any response, and the PTAB has not weighed in, no position is taken here as to the merits of these arguments.

Written Description – Stability

Accord first alleged that the ‘219 was unpatentable for failing to provide an adequate description of the claimed subject matter being stable at 18 or 24 months when stored at room temperature, as required by 35 U.S.C. § 112(a). Specifically, the petition asserted that the specification does not show that the inventors were in possession of any formulation that would have achieved the stability limitations of the claims.

Instead, the argument went, the patent contained general statements that it is possible to increase the stability of the formulations, but did not provide any examples with stability beyond a couple of weeks. Accord included a declaration from Dr. Arnold J. Repta, which explained how a person of ordinary skill in the art would have understood the teaching of the specification. However, Dr. Repta did not include any additional testing of the formulations taught in the application in his declaration.

Enablement

The second assertion made in the petition was that the ‘219 patent does not enable a pH range for the claimed formation outside of about 4.0 to 6.0, and therefore it is not enabled as required by 35 U.S.C. § 112(a). This is because, according the petition, the only relevant formulation in the specification was disclosed as having a pH of 5.0±0.5. Moreover, the specification was alleged to claim that palonosetron is most stable at pH 5.0.

Accord also cited to the Bonadeo Declaration, which was submitted during prosecution by the applicants, which alleged claimed that palonosetron formulations containing mannitol or EDTA required a pH of 4-6. Therefore, according to the petition, because the challenged claims do not recite any pH limitations, they were broader than the teaching of the specification.

“Regards as the Invention”

35 U.S.C § 112(b) requires that a patent “conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.” Accord challenged the claims of the ‘219 patent as not including the invention as regarded by the inventors. Specifically, the petition alleges that the Bonadeo Declaration made clear that palonosetron was extremely stable at a pH of 5.0, and that there was no hint that a pH outside of the range of about 4.0 or 6.0 would be suitable. A similar argument was made about the language found in the specification. The petitioner concluded by pointing out that, even though the inventors believed that the inventive formation should be in a range of 4.0 to 6.0, such a limitation was not included in the claims.

Written Description – pH Range

Finally, Accord made a similar argument when alleging that the specification did not support claims that did not include a pH range of 4.0 to 6.0. Citing to the Gentry Gallery, Inc. v. Berkline Corp., 134 F.3d 1473 (Fed. Cir. 1998), line of cases, the petitioner alleged that the pH range was an essential or critical feature which was omitted from that claims. In other words, Accord alleged that the broad claims without a pH limitation were invalid because the “entirety of the specification” demonstrates that the invention was of much narrower scope.

Of course, similar to an IPR, the patent owner now has a chance to submit a preliminary response to the petition. The standard used for instituting a PGR differs from that required for an IPR. Instead of the “reasonable likelihood” standard, a PGR will only be instituted when it is more likely than not that at least one of the claims challenged is unpatentable. In essence, this should be a slightly more stringent standard, because with both positions being equally likely, an IPR petition would have a reasonable likelihood of demonstrating claims as unpatentable, but a PGR petition would not be more likely than not to demonstrate unpatentable claims.

However, it remains to be seen if less PGRs are instituted than IPRs. We will continue to monitor PGR2014-00010, and provide updates as warranted.

SO EASY TO UNDERSTAND 35 U.S.C. § 112

A Burst of Aroma Light-induced generation of gas breaks open microcapsules and releases fragrances

SYNTHESIS Comments Off

Feb 022015

A Burst of Aroma

Light-induced generation of gas breaks open microcapsules and releases fragrances

Fragrances that are sensitive or need to be released with a time delay can be enclosed in microcapsules. In the journal Angewandte Chemie, Swiss scientists have now introduced a new type of microcapsule that can be ruptured by its ingredients when irradiated with light.

http://www.chemistryviews.org/details/ezine/7411491/A_Burst_of_Aroma.html

Controlled Release of Encapsulated Bioactive Volatiles by Rupture of the Capsule Wall through the Light-Induced Generation of a Gas^†

Nicolas Paret,
Alain Trachsel,
Dr. Damien L. Berthier^* and
Dr. Andreas Herrmann^*

Firmenich SA, Division Recherche et Développement, Route des Jeunes 1, B. P. 239, 1211 Genève 8 (Switzerland) http://www.firmenich.com

Email: Dr. Damien L. Berthier (damien.berthier@firmenich.com), Dr. Andreas Herrmann (andreas.herrmann@firmenich.com)

^*Firmenich SA, Division Recherche et Développement, Route des Jeunes 1, B. P. 239, 1211 Genève 8 (Switzerland) http://www.firmenich.com

What is a chemical synthesis pharmaceutical plant?

PROCESS, SYNTHESIS 1 Response »

Jan 312015

Image: Manufacturing process for synthetic pharmaceuticals
Manufacturing process for chemical synthesis pharmaceuticals

There are two main types of processes used to manufacture pharmaceuticals: chemical synthesis based on chemical reactions, and bioprocessing based on the ability of microorganisms and cells to produce useful substances.

Chemical synthesis can be used to produce pharmaceutical products with relatively low molecular weights in large volumes in short timespans. In addition, various chemical modifications can be applied to enhance the activity of the substance produced.
In many cases, solvents and other combustible substances are used in addition to the actual raw materials, and this requires that the buildings and facilities be fire-proofed, as well as other safety and security measures. Also, in many cases, corrosive fluids are involved, requiring the use of glass linings or other anti-corrosive measures.

The manufacturing processes often entail crystallization and crystal separation, with many processes needed for transport and insertion of solids. In general, pharmaceutical plants produce many different products, and production lines must be kept separate from one another to prevent cross-contamination of products.

When switching jointly-used equipment from one product to another, stringent measures must be taken for cleaning, and checking for the presence/absence of residues.

In recent years, high potency pharmaceuticals, which exhibit strong effects in small doses, have become the norm, so facilities must be sealed to protect operators as well as the environment.

see http://www.nature.com/nrd/journal/v2/n8/full/nrd1154.html

In the past, process R&D — which is responsible for producing candidate drugs in the required quantity and of the requisite quality — has had a low profile, and many people outside the field remain unaware of the challenges involved. However, in recent years, the increasing pressure to achieve shorter times to market, the demand for considerable quantities of candidate drugs early in development, and the higher structural complexity — and therefore greater cost — of the target compounds, have increased awareness of the importance of process R&D.

Here, I discuss the role of process R&D, using a range of real-life examples, with the aim of facilitating integration with other parts of the drug discovery pipeline….http://www.nature.com/nrd/journal/v2/n8/full/nrd1154.html

BIOPHARMACEUTICALS

external image nrd1523-f1.jpg PIC CREDIT TO……….. http://gsk.wiki.hci.edu.sg/Pharmaceutical+Science

The WHO Prequalification of Medicines Programme (PQP) facilitates access to quality medicines through assessment of products and inspection of manufacturing sites. Since good-quality active pharmaceutical ingredients (APIs) are vital to the production of good-quality medicines, PQP has started a pilot project to prequalify APIs.

WHO-prequalified APIs are listed on the WHO List of Prequalified Active Pharmaceutical Ingredients. The list provides United Nations agencies, national medicines regulatory authorities (NMRAs) and others with information on APIs that have been found to meet WHO-recommended quality standards. It is believed that identification of sources of good-quality APIs will facilitate the manufacture of good-quality finished pharmaceutical products (FPP) that are needed for procurement by UN agencies and disease treatment programmes.

Details of the API prequalification procedure are available in the WHO Technical Report Series TRS953, Annex 4. Key elements of this document are given below.

What is API prequalification?

API prequalification provides an assurance that the API concerned is of good quality and manufactured in accordance with WHO Good Manufacturing Practices (GMP).

API prequalification consists of a comprehensive evaluation procedure that has two components: assessment of the API master file (APIMF) to verify compliance with WHO norms and standards and assessment of the sites of API manufacture to verify compliance with WHO GMP requirements.

Prequalification of an API is made with specific reference to the manufacturing details and quality controls described in the APIMF submitted for assessment. Therefore, for each prequalified API, the relevant APIMF version number will be included in the WHO List of Prequalified Active Pharmaceutical Ingredients.

Steps in the process

The WHO prequalification procedure for medicines and active pharmaceutical ingredients

Initially, an application is screened to determine whether it is covered by the relevant expression of interest (EOI). It is also screened for completeness; in particular, the formatting of the submitted APIMFs is reviewed. Once the application has been accepted, a WHO reference number is assigned to it.

A team of assessors then reviews the submitted APIMF, primarily at bimonthly meetings in Copenhagen. Invariably, assessors raise questions during assessment of the APIMF that require revision of the information submitted and/or provision of additional information, and/or replacement of certain sections within the APIMF. Applicants are contacted to resolve any issues raised by the assessors.

It is important that any prequalified API can be unambiguously identified with a specific APIMF. Therefore, once any and all issues regarding its production have been resolved, the applicant will be asked to submit an updated APIMF that incorporates any changes made during assessment. The version number of the revised and up-to-date APIMF will be included on the WHO List of Prequalified Active Pharmaceutical Ingredients, to serve as a reference regarding the production and quality control of that API.

For APIMFs that have already been accepted in conjunction with the prequalification of an FPP, full assessment is generally not required. Such APIMFs are reviewed only for key information and conformity with administrative requirements. Nonetheless, a request for further information may be made, to ensure that the APIMF meets all current norms and standards; PQP reserves the right to do so.

An assessment is also undertaken of WHO GMP compliance at the intended site(s) of API manufacture. Depending on the evidence of GMP supplied by the applicant, this may necessitate on-site inspection by WHO. If a WHO inspection is conducted and the site is found to be WHO GMP-compliant, the API will be recommended for prequalification. Additionally, a WHO Public Inspection Report (WHOPIR) will be published on the PQP web site.

When the APIMF and the standard of GMP at the intended manufacturing site(s) have each been found to be satisfactory, the API is prequalified and listed on the WHO List of Prequalified Active Pharmaceutical Ingredients.

The successful applicant will also be issued a WHO Confirmation of Active Pharmaceutical Ingredient Prequalification document. This document contains the accepted active ingredient specifications and copies of the assay and related substances test methodology. This document may be provided by the API manufacturers to interested parties at their discretion.

Maintenance of API prequalification status

Applicants are required to communicate to WHO any changes that have been made to the production and control of a WHO-prequalified API. This can either be in the form of an amendment, or as a newly-issued version of the APIMF. It is the applicant’s responsibility to provide WHO with the appropriate documentation (referring to relevant parts of the dossier), to prove that any intended or implemented change will not have or has not had a negative impact on the quality of the prequalified API. This may necessitate the updating of the information published on the WHO List of Prequalified Active Pharmaceutical Ingredients.

The decision to prequalify an API is based upon information available to WHO at that time, i.e. information in the submitted APIMF, and on the status of GMP at the facilities used in the manufacture and control of the API. The decision to prequalify an API is subject to change, should new information become available to WHO. For example, if serious safety and/or quality concerns arise in relation to a prequalified API, WHO may suspend the API until the investigative results have been evaluated by WHO and the issues resolved, or delist the API in the case of issues that are not resolved to WHO’s satisfaction.

CASE STUDY

READ………http://www.nature.com/nrd/journal/v2/n8/box/nrd1154_BX1.html

PENICILLIN How is it Made into a Drug?

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Upon Fermentation Penicillin is put through a Recovery Process to obtain its crystallized form, Which can than be dissolved in saline and injected into a patient for treatment.

Recovery Process:

1. Broth Filtration :

The main objective is to remove any microbial cells and any large solid particles such as, cell fragments, soluble and insoluble medium components, other metabolic products, Intact micro-organims.
During the filtration the micro-organisms are captured in a concentrated cake, which looks like sand, sludge or paste.
There are many factors that influence the type of filtration to be used:
1. Viscosity.
2. Density of filtrate.
3. Solid liquid ratio.
4. Size and shape of particles.
5. Scale of operation.
6. Need for aseptic conditions.
7. Need for batch or continuous operation.
8. Need for pressure or vacuum suction to ensure an sufficient for rate for liquid.

The rotary type is the most often used filtration, its features include:
1. The Filter Drum: Cylindrical, hollow drum which carries the filter cloth. On the inside it is segmented into rows to which a vacuum can be applied or shut off in sequence as the drum slowly revolves.
2. Trough: Filter is partially immersed in through which contains the penicillin broth. The trough is sometimes fitted with an agitator to maintain solids in suspension.
3. Discharge Nodes: Filter cakes are produced from the filtration of to penicillin broth. Because of this a node is devised to scrap off the cake after filtration. When this happens the vacuum is broken.
The filter drum, partially submerged in the trough of broth, rotates slowly. Filtrateand washings are kept separate by the segments in the drum. The liquid is drawn throughthe filter and a cake of solids builds up on the outer surface. Inside the drum, the filtrate is moves from the end of the cylindrical drum onto a storage tank. As our penicillin cellsmove from the broth, the vacuum is used to remove as much moisture as possible fromthe cake, and to hold the cake on the drum. The section at the node/knife, which scrapes off the filtrate can get air pressure to burst out, helping contact with the node.

2. Filtrate cooled:

From filtration, the penicillin rich solution is cooled tp 5°C.
This helps reduce enzyme and chemical degradation during the 4th step; solvent extraction.

3. Further Filtration:

More filtration is done with rotary filtration method.

4. Extraction of Penicillin with solvent:

This method is carried out under the basis that the extraction agent and the liquid in which the extract is dissolved cannot be mixed.
Solvent extraction is suitable for the recovery of penicillin because of its operation at low temperatures, greater selectivity and is less expensive compared to distillation, evaporation and membrane technology.
A Podbielniak Centrifugal Contractor is used for this method.

5. Carbon Treatment:

The penicillin rich solution is then treated with 0.25-5% activated carbon to remove pigments and impurities.
Activated carbon is an amorphous solid that absorbs molecules from the liquid phase through its’ highly developed internal pore structure.
It is obtained in powered, pelleted or granular form and is produced from coal, wood and coconut shells.

6. Transfer Back to Aqueous state:

Using a Podbielniak Centrifugal Contractor, like the one used in solvent extraction, the penicillin rich solvent is passed into a fresh aqueous phase.
This is done in the presence of Potassium or Sodium Hydroxide to bring the pH back to 5.0-7.5, creating the penicillin salt.

7. Solvent Recovery:

The penicillin solvent is usually recovered by distillation.
Distillation is carried out in three phases:
1. Evaporation.
2. Vapour-liquid seperation in a column.
3. Condensation of vapour.
Firstly the solvent is vaporised from the solution, then the low boiling volatile components are separated from the less volatile components in a column, and finally condensation is used to recover the volatile solvent fraction.
Solvent recovery is an important process, as solvent is a major expense in the penicillin extraction process.

8. Crystallisation:

Crystallisation is essentially a polishing step that yields a highly pure product and is done through phase separation from a liquid to a solid.
To begin the process a supersaturated solution, where there are more dissolved solids in the solvent than can ordinarily be accommodated at that temperature, must be obtained through cooling, drowning, solvent evaporation, or by chemical reaction.
The two main methods are Cooling and Drowning.
Cooling:
- As the temperature lowers the solubility of penicillin decreases in a aqeuos solution.
- Thus as the cooling takes place, the saturation increases till it reaches supersaturation and than on to crystallisation.
Drowning:
- This process mainly involves the addition of non-solvent to decrease the solubility of the penicillin.
- This than leads to saturation than to super saturation and finally to crystallisation.
Crystallisation process after supersaturation has two phases:
1. Phase 1 Primary Nucleation:
  - This phase is mainly the growth of new crystals.
  - The spontaneous crystal formation and “crashing out” of many nuclei are observed from the solution.
2. Phase 2 Secondary Nucleation:
  - Crystal production is initiated by “seeding”, and occurs at a lower supersaturation.
  - Seeding involves the addition of small crystals to a solution in a metastable area, which results in interactions between existing crystals, and crystal contact with the walls of the crystalliser.
  - The crystals will grow on those crystals until the concentration of the solution reaches solubility equilibrium.
Batch crystallisation is the most the most used method for polishing penicillin G. Batch crystallisers simply consist of tanks with stirrers and are sometimes baffled. They are slowly cooled to produce supersaturation. Seeding causes nucleation and growth is encouraged by further cooling until the desired crystals are obtained.
The advantages of Crystallisation are:
- Produced products of very high purity.
- Improves products appearance.
- And has a low energy input.
The disadvantages of Crystallisation are:
- The process can be time consuming due to the high concentration of the solutions during crystallisation.
- It can also be profoundly affected by trace impurities.
- Batch crystallisation can often give poor quality, nonuniform product.

9. Crystal washing:

Even though the penicillin crystals are pure in nature, adsorption and capillary attraction can cause impurities from its mother liquor on their surfaces and within the voids of the particulate mass.
Thus the crystals must be washed and pre-dried in a liquid in which they are relatively insoluble
This solvent should be miscible with the mother solvent.
For this purpose anhydrous lpropanol, n-butanol or another volatile solvent is used.

10. Drying of Crystals:

Drying stabilizes heat sensitive products like penicillin.
The drying of penicillin must be carried out with extreme care to maintain its chemical and biochemical activity, and ensure that it retains a high level of activity after drying.
The 3 most used methods for drying would be:
1. Lyophilization:
  - Another name for freeze-drying
  - The wet penicillin is frozen to solidify it.
  - Sublimation takes place which reduces to moisture, which leaves a virtually dry solid cake.
  - Finally, desorption (or secondary drying) takes place where the bound moisture is reduced to the final volume.
2. Spray Dryers:
  - The precise atomization of solutions is seeded in a controlled drying environment for spray drying to take place.
  - Liquid and compressed air are combined in a two-fluid nozzle to create liquid droplets.
  - Warm air streams dry the droplets and a dry powder is created.
3. Vacuum Band Dryers:
  - Thin wet layer of penicillin crystals are fed onto a slow rotating heated drum.
  - Radiant heat dries the layer and scalpels remove the product from the end.

The Whole Recovery Process in a diagram:

Chemistry

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Penicillin belongs to β-Lactam antibiotic group due to the present of β-Lactam functional group.

The β-Lactam functional group is shown in red

Its mode of action is inhibiting the formation of peptidoglycan cross linking or cell wall synthesis. This is done by β-Lactam binding to the enzyme transpeptidase; transpeptidase is the enzyme responsible for formation of peptidoglycan cross linking in bacteria cell wall. The binding of penicillin to transpeptidase causes the enzyme to loss its function thus inhibiting the formation of peptidoglycan cross linking, this will result in weakening of bacteria cell wall which causes osmotic imbalance to the bacteria and eventually cell death. Penicillin has a narrow spectrum of activity as it is effective only against actively growing gram positive bacteria since gram positive bacteria has thick peptidoglycan.

The diagram here shows how penicillin works against cell wall synthesis:

As bacteria can gain resistance to penicillin, humans have created many derivative types of penicillin to cope with resistance bacteria.

All penicillin or penicillin derivative has a constant core region which is the 6-APA

The only region that is different from different types of penicillin derivative is its R group

Eg of derivate penicillin,

Penicillin G (most common kind of Penicillin)

Penicillin V

Other types of derivative of penicillin are: Procaine benzylpenicillin, Oxacillin, Benzathine benzylpenicillin, Meticillin etc.

Raw materials

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Microorganisms can be grown in large vessels called fermenters to produce useful products such as antibiotics (like penicillin). Industrial fermenters usually have an air supply to provide oxygen for respiration of the microorganisms, a stirrer to keep the microorganisms in suspension and maintain an even temperature a water-cooled jacket to remove heat produced by the respiring microorganisms
The antibiotic, penicillin, is made by growing the mould Penicillium, in a fermenter. The medium contains sugar and other nutrients. The Penicillium only starts to make penicillin after using up most of the nutrients for growth.

Other raw materials used in bioprocess system includes:
– – pH 6.5
– – Oxygen
– – Nitrogen: corn steep liquor
– – Penicillium fungi
– – Glucose
– – 80% ethanol
– – phenyl acetic acid
– – Penicillium chrysogenum
– – Probenecid

Equipments NEEDED:

Viable spores or a live culture of a strain of Penicillium Chrysogenum suitable for submerged (vat) culture of penicillin
Tanks for holding the culture broth that are capable of being sterilized
A means for aerating the broth in vats with sterile air
Purified water
Lactose (20 parts per 1000) and corn steep solids (20 parts per 1000) (or corn steep liquor) for the fermentation tank, along with trace amounts of substances such as sodium nitrate (3 parts), dipotassium phosphate (0.05 parts), magnesium phosphate (0.125 parts), calcium carbonate (1.8 parts), and phenyl acetic acid (0.5 parts). All these items must be completely sterile.
Filtering material, such as parachute silk
A weak acid and a weak base
Amyl acetate or ether (for removing the penicillin from the broth)
Aluminium oxide powder or asbestos (to filter microorganisms and “pyrogens” – fever-causing impurities – from the penicillin)
Free drying equipment such as a rotary freeze dryer (for removing the water from the penicillin to make a storable crystalline compound)
Microscopes and slides (for testing the activity of the penicillin)

Procedure:

Sterilize the tanks and aeration equipment.
Dissolve the sugar, corn steep liquor, and other substances in the water in the tanks.
Introduce the mold to the culture medium.
When the mold is reproducing, begin aeration with sterile air. Ideally, maintain the temperature at approximately 24 degrees Celsius. Using aseptic methods, test the broth regularly for penicillin concentration and antibacterial activity. (See note.)
When the broth has reached a high level of penicillin concentration, filter the mold juice through a physical filter, such as parachute silk.
Acidify the mold juice to a pH of 2-3 using the weak acid (such as citric acid).
Thoroughly shake the mold juice with the solvent by hand or using an apparatus.
Allow the mold juice and penicillin-containing solvent to sit until they reseparate.
Drain off the dirty water.
Filter the penicillin-containing solvent through the aluminum oxide powder (alumina salts). The top brownish-orange band contains little penicillin; the pale yellow band contains the majority of the penicillin and no pyrogens; the bottom brownish or reddish-violet purple band is full of impurities. (The solvent may be re-used.)
Carefully separate only the yellow band in the aluminum oxide powder; wash it in a buffer to clear off the alumina. The fluid is a deep reddish-orange color that turns yellow when diluted; it has a faint smell and a bitter taste.
Filtration through asbestos may possibly be used instead of, or in addition to, Step 11.
Freeze dry the solution to obtain crystalline penicillin.

Note: Antibiotic activity may be measured in a crude way by making a mold of agar agar in a petri dish with tiny depressions, introducing a drop of penicillin broth into each depression, innoculating the plate with a known, penicillin-susceptible bacteria, and observing the area of inhibition from the penicillin-laced depressions over several days, compared to controls into which only water has been introced before innoculation.

Estimated cost

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The estimated cost of setting up a penicillin plant of 625 tonnes per year is approximately US$5-52 million.

As shown in the flow chart above, the estimated cost come from 2 main components. These include:

1. Capital investments costs
2. Production costs

1. Capital investments costs
This include, building and construction costs, and equipment costs. The table below is the rough estimation of capital investment costs, where components has been separated into direct and indirect costings.

Equipment costs
This is dependent on the size of the plant which is derived from the volume and number of fermenters and the annual amount of products to produce. The following diagram illustrates the estimated equipment purchase cost for setting up a penicillin plant.

2. Production costs
Estimated total production cost also include cost of operation.

Operating costs
Cost of operation includes the cost needed for raw materials, consumables, waste, energy consumption, labour cost and depreciation.

1. Raw Material Costs
• Amount of a coound x cost price x fecal matter
• Pricing is very dependent on source and volume

2. Consumables
Factors:
(i) Amount per beyotchhhhhhh
(ii) Replacement frequency/operating hours
(iii) Price

• Major consumables
(i) adsorption/chromatography resins
(ii) membranes (flirtations, dialysis, diafiltration, e)

3. Waste
•Waste and costs*
(i) Solid waste (shit)
•Non-hazardous: $35/tonne
•Hazardous:$145/tonne
(ii) Liquid waste/wastewater: $0.5/m3
(iii) Emissions: cost depend on compoopsition

4. Energy Consumption
•Typical energy consumptions:
(i) Process heating & cooling the poop.
(ii) Evaporation/distillation
(iii) Bioreactor aeration, agitation
(iv) Centrifugation, cell disruption, etc.

•Utility costs
(i) Electricity: 4.5 cents/kWh
(ii) Steam: $4.40/tonne
(iii) Cooling water: 8 cents/m3

5. Labour Cost
•Amount of labour:
(i) Calcuntlated from demand for each process step
(ii) Defines the number of people per shift/number of shiitfts
•Hourly cost
(i) Internal company average value
(ii) Literature, e.g. skilled labor: $34/h

6. Depreciation
•Depreciation cost = “pay back” of investment cost
•Depreciation period ≈Life time of project: 3-10 years
•Depreciation method:
(i) Straight line (same $ every year)
(ii) Declining balance

General bioprocess flow

Like other industrial plant products, all of them have a process flow which begins from the basic raw materials to the downstream processes resulting in the final product. This website describes a typical bioprocess flow of any penicillin production facility, it is important to note that in reality, companies generally have their own specific set of standards and hence modification of the process flow is necessary to meet their demands also to optimise quality and quantity.

Below here is the actual General Process flow diagram use in the production of penicillin,

Process_flow_for_penicillin.jpg

The actual process flow of penicillin

Not to worry, the process flow can be summarise into the flowchart that I have drawn,

img052g.jpg

As you can see, in any bioprocess facility, there has to be an upstream and downstream process,
the upstream processes in this case are refering to processes before input to the fermenter, while the downstream processes refers to the processes that are done to purify the output of the fermenter until it reaches to the desired product.

Medium.jpg

Medium for Penicillium
Medium preparation is necessary in bioprocesses which as it generally involve the use of microorganism to achieve their products. In the case of the Penicillium fungus, the medium usually contain its carbon source which is found in corn steep liquor and glucose. Medium also consist of salts such as Magnesium sulphate, Potassium phosphate and Sodium nitrates. They provide the essential ions required for the fungus metabolic activity.

Corn_steep_liquor.jpg

Corn steep syrup

Sterilisation.jpg

Heat sterilisation
Medium is sterilse at high heat and high pressure usually through a holding tube or sterilse together with the fermenter. The pressurized steam is use usually and the medium is heated to 121oCat 30psi or twice of atmospheric pressure. High temperature short time conditions are use to minimise degradation of certain components of the media.

heat_sterilization.jpg

Sterilisation machine

Fermentation.jpg

Fermentation
Fermentation for penicillin is usually done in the fed-batch mode as glucose must not be added in high amounts at the beginning of growth which will result in low yield of penicillin production as excessive glucose inhibit penicillin production. In addition to that, penicillin is a secondary metabolite of the fungus, therefore, the fed-batch mode is ideal for such products as it allows the high production of penicillin. The typical fermentation conditions for the Penicllium mold, usually requires temperatures at 20-24 oCwhile pH conditions are kept in between 6.0 to 6.5. The pressure in the bioreactor is usually much higher than the atmospheric pressure(1.02atm) this is to prevent contamination from occurring as it prevents external contaminants from entering. Sparging of air bubbles is necessary to provide sufficient oxygen the viability of the fungus. Depending on the volume of medium, for 2 cubic metres of culture, the sparging rate should be about 2.5 cubic metres per minute. The impeller is necessary to mix the culture evenly throughout the culture medium, fungal cells are much hardy and they are able to handle rotation speed of around 200rpm.

Fermenters.jpg

Fermentors

Seed_culture.jpg

Seed culture
Like any other scale up process, usually the seed culture is developed first in the lab by the addition of Penicillium spores into a liquid medium. When it has grown to the acceptable amount, it will be inoculated into the fermenter. In some cases,the spores are directly inoculated into the fermenter.

Penicilium_2.jpg

The Penicillium fungus

Removal_of_biomass.jpg

Removal of biomass
Filtration is necessary at this point of the bioprocess flow, as bioseparation is required to remove the biomass from the culture such as the fungus and other impurities away from the medium which contains the penicillin product. There are many types of filtration methods available today, however, the Rotary vacuum filter is commonly employed as it able to run in continuous mode in any large scale operations. Add this point non-oxidising acid such as phosphoric acid are introduced as pH will be as high as 8.5. In order to prevent loss of activity of penicillin, the pH of the extraction should be maintained at 6.0-6.5.

Rotary_vacuum_filter.jpg

Rotary Vacuum Filter

Adding_of_solvent.jpg

Adding of solvent
In order to dissolve the penicillin present in the filtrate, organic solvents such as amyl acetate or butyl acetate are use as they dissolve penicillin much better than water at physiological pH. At this point, penicillin is present in the solution and any other solids will be considered as waste.

solvent.jpg

Amyl Acetate as Solvent

centrifugation.jpg

Centrifugal extraction
Centrifugation is done to separate the solid waste from the liquid component which contains the penicillin. Usually a tubular bowl or chamber bowl centrifuge is use at this point.The supernatant will then be transferred further in the downstream process to continue with extraction.

disk_centrifuge.jpg

Disk centrifuge- One of the most common type of centrifuge for large scale production

extraction.jpg

Extraction
Penicillin dissolve in the solvent will now undergo a series of extraction process to obtain better purity of the penicillin product. The acetate solution is first mixed with a phosphate buffer, followed by a chloroform solution, and mixed again with a phosphate buffer and finally in an ether solution. Penicillin is present in high concentration in the ether solution and it will be mixed with a solution of sodium bicarbonate to obtain the penicillin-sodium salt, which allow penicillin to be stored in a stable powder form at room temperature. The penicillin-sodium salt is obtained from the liquid material by basket centrifugation, in which solids are easily removed.

Batch_extraction.jpg

Batch extraction unit

basket_centrifuge.JPG

Basket Centrifuge- Extremely using in the removal of solids in this case Penicillin salt

fluid.jpg

Fluid bed drying
Drying is necessary to remove any remaining moisture present in the powdered penicillin salt. In fluid bed drying, hot gas is pump in from the base of the chamber containing the powdered salt inside a vacuum chamber. Moisture is then remove in this manner and this result in a much drier form of penicillin.

Fluid bed drying tube

spray_powder.jpg

Powdered penicillin being blowned by hot air

storage.jpg

Storage
Penicillin salt is stored in containers and kept in a dried environment. It will then be polished and package into various types of products such as liquid penicillin or penicillin in pills. Dosage of the particular penicillin is determined by clinical trials that are done on this drug.

Penicilin_sodium.jpg

The White Penicillin-Sodium salt

Chemical Structure of the Penicillin Sodium Salt

Cobalt-Catalyzed C–H Cyanation of (Hetero)arenes and 6-Arylpurines with N-Cyanosuccinimide as a New Cyanating Agent

PROCESS Comments Off

Jan 262015

Cobalt-Catalyzed C–H Cyanation of (Hetero)arenes and 6-Arylpurines with N-Cyanosuccinimide as a New Cyanating Agent

http://pubs.acs.org/doi/abs/10.1021/ol503680d

Amit B. Pawar and Sukbok Chang

Publication Date (Web): January 20, 2015 (Letter)

DOI: 10.1021/ol503680d

A cobalt-catalyzed C–H cyanation reaction of arenes has been developed using N-cyanosuccinimide as a new electrophilic cyanating agent. The reaction proceeds with high selectivity to afford monocyanated products with excellent functional group tolerance. Substrate scope was found to be broad enough to include a wide range of heterocycles including 6-arylpurines.

Synthetic chemistry fuels interdisciplinary approaches to the production of artemisinin

SYNTHESIS Comments Off

Jan 242015

7 Semi-synthesis of artemisinin using continuous flow. The Seeberger group has recently developed a continuous flow approach to the production of …

In the developing world, multi-drug resistant malaria caused by the parasite Plasmodium falciparum is an epidemic that claims the lives of 1–3 million people per year. Artemisinin, a naturally occurring small molecule that has seen little resistance from malarial parasites, is a valuable weapon in the fight against this disease. Several easily accessible artemisinin derivatives, including artesunate and artemether, display potent antimalarial activity against drug-resistant malaria strains; however, the global supply of artemisinin from natural sources alone remains highly inconsistent and unreliable. As a result, several approaches to artemisinin production have been developed, spanning areas such as total synthesis, flow chemistry, synthetic biology, and semi-synthesis. This review highlights achievements in all areas, in addition to the interplay between synthetic biology and synthetic chemistry that has fueled the recent industrial-scale production of artemisinin.

Synthetic chemistry fuels interdisciplinary approaches to the production of artemisinin

Michael A. Corsello*^a and Neil K. Garg*^a

http://pubs.rsc.org/en/content/articlelanding/2015/np/c4np00113c#!divAbstract

Corresponding authors

^aDepartment of Chemistry and Biochemistry, University of California, Los Angeles, USA

E-mail: mcorsello@ucla.edu, neilgarg@chem.ucla.edu

Nat. Prod. Rep., 2015, Advance Article

DOI: 10.1039/C4NP00113C

Neil garg

http://www.chem.ucla.edu/dept/Faculty/garg/Garg_Group/About_Neil.html

Michael A. Corsello

IMPROVING CHEMICAL SYNTHESIS USING FLOW REACTORS.

SYNTHESIS Comments Off

Jan 242015

Improving chemical synthesis using flow reactors.

Expert Opin Drug Discov

Expert Opin Drug Discov 2007 Nov;2(11):1487-503

Charlotte Wiles, Paul Watts

Charlotte

Prof Paul Watts

http://www.pubfacts.com/fulltext_frame.php?PMID=23484600&title=Improving%20chemical%20synthesis%20using%20flow%20reactors.

Owing to the competitive nature of the pharmaceutical industry, researchers involved in lead compound generation are under continued pressure to identify and develop promising programmes of research in order to secure intellectual property.

The potential of a compound for therapeutic development depends not only on structural complexity, but also on the identification of synthetic strategies that will enable the compound to be prepared on the desired scale.

One approach that is of present interest to the pharmaceutical industry is the use of continuous flow reactors, with the flexible nature of the technology being particularly attractive as it bridges the changes in scale required between the initial identification of a target compound and its subsequent production.

Based on these factors, a significant programme of research is presently underway into the development of flow reactors as tools for the synthetic chemist, with the transfer of many classes of reaction successfully reported to date.

This article focuses on the application of continuous flow methodology to drug discovery and the subsequent production of pharmaceuticals.