Catalyst- and additive-free Baeyer–Villiger-type oxidation of α-iodocyclopentenones to α-pyrones: using air as the oxidant

green chemistry, spectroscopy, SYNTHESIS, Uncategorized Comments Off

Oct 152019

Graphical abstract: Catalyst- and additive-free Baeyer–Villiger-type oxidation of α-iodocyclopentenones to α-pyrones: using air as the oxidant

An efficient synthetic approach for the synthesis of α-pyrones via Baeyer–Villiger-type oxidation of α-iodocyclopentenones through a catalyst- and additive-free system using air as an environmentally benign oxidant is described. The reaction exhibits excellent functional group compatibility and provides a simple and efficient protocol for the construction of highly functionalized α-pyrones under mild reaction conditions.

Catalyst- and additive-free Baeyer–Villiger-type oxidation of α-iodocyclopentenones to α-pyrones: using air as the oxidant†

Yuanyuan Zhou,^a Xianxiao Chen,^a Xiangxiang Ling^a and Weidong Rao

*^a

Author affiliations

*Corresponding authors

^aJiangsu Key Laboratory of Biomass-based Green Fuels and Chemicals, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China
E-mail:weidong@njfu.edu.cn

6-Cyclohexyl-4-phenyl-2H-pyran-2-one (2e)[S3]

Product 2e was obtained as a pale-yellow solid in 68% yield (52 mg) following the general procedure, mp 96-97 °C;

1H NMR (600 MHz, CDCl3) δ 7.58-7.56 (m, 2H), 7.48-7.46 (m, 3H), 6.34 (d, J = 1.3 Hz, 1H), 6.26 (d, J = 0.8 Hz, 1H), 2.48 (tt, J = 11.8, 3.3 Hz, 1H), 2.04-2.01 (m, 2H), 1.87-1.84 (m, 2H), 1.47 (qd, J = 12.5, 3.0 Hz, 2H), 1.39-1.32 (m, 2H), 1.28-1.23 (m, 2H);

13C NMR (150 MHz, CDCl3) δ 169.8, 163.6, 155.6, 136.2, 130.5, 129.1, 126.7, 108.4, 100.9, 42.5, 30.6, 25.9, 25.8

http://www.rsc.org/suppdata/c9/gc/c9gc02725d/c9gc02725d1.pdf

/////////https://pubs.rsc.org/en/Content/ArticleLanding/2019/GC/C9GC02725D?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

EP Patent Validation Service

PATENTS, Uncategorized Comments Off

Sep 062019

Traditional route

The conventional route for EP patent validation is for the client to instruct their EP attorneys to execute the validation. The EP attorneys would then instruct a validations provider (like us) or perform the validations themselves using attorney partners in each country who they use based on a reciprocity model, which is usually not cost or quality selective. The EP attorneys would add significant fees for each country.

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linkedin.com/in/sandeep-mishra-35b215b

scienceinfoware@gmail.com

///////////Sandeep Mishra, Director, e Science Infoware, ep, patent

Engineering of a fungal laccase to develop a robust, versatile and highly-expressed biocatalyst for sustainable chemistry

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Sep 042019

Engineering of a fungal laccase to develop a robust, versatile and highly-expressed biocatalyst for sustainable chemistry

Felipe de Salas, Pablo Aza, Joan F. Francesc Gilabert, Gerard Santiago, Sibel Kiliç, Mehmet Emre Şener, Jesper Vind, Victor Guallar, Angel T. Martínez and Susana Camarero

Abstract

Fungal laccases can play an important role as biocatalysts in organic chemistry to replace chemical synthesis. In a previous work we synthesized conductive polyaniline using a high-redox potential laccase from our collection of recombinant fungal variants. Still, the oxidation of aniline is hindered by the reaction conditions (low pH and presence of anionic surfactants). Thus, we tackle here the directed evolution of the enzyme asisted by computational simulation aiming at improving aniline oxidation at the required polymerization conditions while maintaining the enzyme´s substrate promiscuity. Simultaneously, its secretion by the host used for the engineering (Saccharomyces cerevisiae) was enhanced. Then, the improved laccase variant was overproduced in the industrial host Aspergillus oryzae and assayed for one‐pot synthesis of polyaniline and naphtol-derived dyes whose textile dyeing properties were verified in an industrial environment. Finally, modification of its C-terminal tail further enhanced laccase stability by flexibilization of the region. The resulting biocatalyst displays noticeable stability at high temperature and extreme pH while shows improved kcat values on the different substrates tested. Moreover, it is remarkably produced in S. cerevisiae at rates not formerly reported in the literature. These facts, together with the overexpression in A. oryzae opens new scenarios for its further development and application.

Enzyme production and purification Laccase was produced by S. cerevisiae 1 L-flask cultures and purified as described before.5 Laccase activity in the culture was measured spectrophotometrically with 3 mM ABTS in 100 mM citrate-phosphate buffer, pH 3 by the increase of Absorbance 418 nm (ε418 = 36000 M−1 cm−1). One activity unit (U) was defined as the amount of enzyme needed to transform 1 µmol substrate/minute. To estimate enzyme production, enzyme concentration of a purified laccase variant was measured by the A280 (Nanodrop 2000, Thermofisher, USA) and the specific activity (U/mg) was calculated and used to deduce the mg of enzyme/l obtained in the culture. Enzyme characterization All characterization assays were performed with purified enzymes.

////////

https://pubs.rsc.org/en/content/articlepdf/2019/gc/c9gc02475a

Design, synthesis and antimicrobial activity of usnic acid derivatives

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Feb 012019

Design, synthesis and antimicrobial activity of usnic acid derivatives

Victor Kartsev,^a Boris Lichitsky,^b Athina Geronikaki,*^c Anthi Petrou,^c Marija Smiljkovic,^d Marina Kostic,^d Oliver Radanovic^e and Marina Soković^d

Author affiliations

*Corresponding authors

^aInterBioscreen, Moscow, Russia

^bZelinsky Institute of Organic Chemistry, Leninsky Prospect, Moscow, Russia
E-mail: blich2006@mail.ru

^cSchool of Health, Department of Pharmacy, Aristotle University of Thessaloniki, Greece

^dMycological Laboratory, Department of Plant Physiology, Institute for Biological Research, Siniša Stanković, University of Belgrade, Bulevar Despota Stefana 142, Belgrade, Serbia

^eScientific Institute of Veterinary Medicine of Serbia, ul. Vojvode Toze 14, 11000 Belgrade, Serbia

Abstract

Usnic acid, a dibenzofuran, was originally isolated from lichens producing secondary metabolites, and is well known as an antibiotic, but is also endowed with several other interesting properties. Thus, the goal of this paper is the design of new usnic acid derivatives and evaluation of their antimicrobial activity. All newly synthesized compounds possess good antibacterial activity with MIC ranging from 1.02–50.93 × 10⁻² mmol mL⁻¹ and MBC from 2.05–70.57 × 10⁻² mmol mL⁻¹. The most sensitive bacterial species was Staphylococcus aureus, while Pseudomonas aeruginosa and Escherichia coli were the most resistant among the ATCC strains, and MRSA was the most resistant among all tested bacteria (ATCC and clinical isolates). Their antifungal activity was very strong (MIC = 0.35–7.53 × 10⁻² mmol mL⁻¹ and MFC = 0.70–15.05 × 10⁻² mmol mL⁻¹) – better than those of reference compounds and usnic acid itself. The most sensitive fungal species was Trichoderma viride, while Penicillium versicolor var. cyclopium appeared to be the most resistant. It should be mentioned that in general most of the compounds showed weaker antibacterial activity, but better antifungal properties than usnic acid itself. The results allow us to conclude that the title compounds are good lead compounds for novel more active antibacterial drugs. On the other hand, these compounds are very promising as antifungals.

https://pubs.rsc.org/en/content/articlelanding/2018/md/c8md00076j#!divAbstract

////////////Usnic acid, dibenzofuran

Kalyan Kumar Pasunooti, Novel Tetrazole-Containing Analogues of Itraconazole as Potent Antiangiogenic Agents with Reduced Cytochrome P450 3A4 Inhibition

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Jan 052019

Itraconazole has been found to possess potent antiangiogenic activity, exhibiting promising antitumor activity in several human clinical studies. The wider use of itraconazole in the treatment of cancer, however, has been limited by its potent inhibition of the drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4). In an effort to eliminate the CYP3A4 inhibition while retaining its antiangiogenic activity, we designed and synthesized a series of derivatives in which the 1,2,4-triazole ring is replaced with various azoles and nonazoles. Among these analogues, 15n with tetrazole in place of 1,2,4-triazole exhibited optimal inhibition of human umbilical vein endothelial cell proliferation with an IC₅₀ of 73 nM without a significant effect on CYP3A4 (EC₅₀ > 20 μM). Similar to itraconazole, 15n induced Niemann-Pick C phenotype (NPC phenotype) and blocked AMPK/mechanistic target of rapamycin signaling. These results suggest that 15n is a promising angiogenesis inhibitor that can be used in combination with most other known anticancer drugs.

Novel Tetrazole-Containing Analogues of Itraconazole as Potent Antiangiogenic Agents with Reduced Cytochrome P450 3A4 Inhibition

Yingjun Li^†^§, Kalyan Kumar Pasunooti^†^§, Ruo-Jing Li^†, Wukun Liu^†, Sarah A. Head^†, Wei Q. Shi^†

, and Jun O. Liu*^†^‡

^†Department of Pharmacology and Molecular Sciences and ^‡Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States

J. Med. Chem., 2018, 61 (24), pp 11158–11168

DOI: 10.1021/acs.jmedchem.8b01252

Publication Date (Web): November 27, 2018

*E-mail: joliu@jhu.edu. Phone 410-955-4619. Fax 410-955-4520.

https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01252

■ ASSOCIATED CONTENT *S Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.8b01252. Molecular formula strings (CSV) Detail of synthesis procedures; kinetic curve of CYP3A4 enzyme activities; philipin staining of compound 15c, 15g; competition assay of itraconazole photoaffinity probe; and NMR and HPLC chart of representative compounds (PDF)

■ AUTHOR INFORMATION Corresponding Author *E-mail: joliu@jhu.edu. Phone 410-955-4619. Fax 410-955- 4520. ORCID Wei Q. Shi: 0000-0001-5453-1753 Jun O. Liu: 0000-0003-3842-9841 Author Contributions § Y.L. and K.K.P. contributed equally to this work. Notes The authors declare no competing financial interest.

■ ACKNOWLEDGMENTS This work was supported by the National Cancer Institutes (grant R01CA184103) and the Flight Attendant Medical Research Institute

4-(4-(4-(4-(((2S,4R)-2-((1H-Tetrazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)- 1-sec-butyl-1H-1,2,4-triazol-5(4H)-one (15n).

1 H NMR (500 MHz, CDCl3, δH): 8.46 (s, 1H), 7.61 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 9 Hz, 2H), 7.24 (dd, J = 8.5, 2.0 Hz, 1H), 7.03 (d, J = 9.0 Hz, 2H), 6.81 (d, J = 9.0 Hz, 2H), 5.36 (d, J = 14.0 Hz, 1H), 5.27 (d, J = 14.0 Hz, 1H), 4.38 (t, J = 5.0 Hz, 1H), 4.31−4.27 (m, 1H), 3.95 (dd, J = 8.5, 6.5 Hz, 1H), 3.88−3.83 (m, 2H), 3.53 (dd, J = 9.5, 6.5 Hz, 1H), 3.38 (br s, 4H), 3.26 (br s, 4H), 1.89−1.83 (m, 1H), 1.74−1.69 (m, 1H), 1.39 (d, J = 7.0 Hz, 3H), 0.90 (t, J = 7.5 Hz, 3H).

13C NMR (125 MHz, CDCl3, δC): 162.5, 152.8, 152.7, 152.0, 136.3, 133.9, 133.3, 131.5, 130.1, 129.6, 127.2, 123.6, 116.8, 115.4, 107.4, 74.8, 67.9, 67.6, 56.6, 52.7, 36.5, 31.0, 28.5, 19.2, 10.8.

HRMS (ESI) calcd for C34H37Cl2N9O4, 706.2424; found, 706.2425.

HPLC purity: 95.9%, tR = 10.5 min

Kalyan Kumar Pasunooti,

kalyan kumar <kalyandrf@gmail.com>

Dr. Kalyan Kumar Pasunooti pursued his PhD degree from Nanyang Technological University (NTU) (www.ntu.edu.sg), Singapore (2007 – 2011) in the field of Medicinal, Peptide & Protein chemistry. His graduate research work is focused on “Synthesis of bioactive amino acid building blocks and their applications towards the peptides and glycopeptides.” His have total 16 years of academic and industry experience with major multinationals companies & academic institutions and have worked with many collaborative professors around the globe. He authored with more than 28 international peer-reviewed high impact publications such as PNAS, Wily (Angew Chemie), RSC (Chem Comm and Org Biomol Chem), most of American Chemical Society journals (Journal of American Chemical Society, Org. Lett., ACS Chem Bio, J Comb Chem and Bioconugate Chem) and Elsevier (Tetrahedron Letters) journals which are featured many times in Chem. Eng. News and other journals. He holds American patent while work with Johns Hopkins-School of Medicine, USA and this molecule in phase II clinical trials for treating cancer.

Prior to his graduate studies, he spent 5 years as a research scientist in reputable research organizations namely GVK Bio, India (www.gvkbio.com) (2006-2007) and Dr. Reddy’s Laboratories Ltd (www.drreddys.com) (2003-2006) in India. After his PhD graduation, he worked for world leading research institutes such as Johns Hopkins-School of Medicine, USA (www.hopkinsmedicne.org) (2012-2013), Nanyang Technological University-NTU, Singapore) (www.ntu.edu.sg) (2013 – 2017) and Singapore MIT Alliance for research & Technology-SMART (www.smart.mit.edu) (2017–2018). His research interests focused on development of next generation biologically relevant peptide & protein therapeutics using their newly discovered methodologies for biomedical applications.

He has excellent skills in designing synthesis, purification and characterization of complex peptide and small molecules for medicinal chemistry applications. He gained extensive experience in Medicinal, Carbohydrate, Peptide & Protein and nucleotide & nucleoside Chemistry and familiar with modern methods and experienced in designing & executing synthesis for various bioactive peptide and small molecule inhibitors. He well versed in synthesis and characterization of complex organic molecules and with the analytical data interpretation.

Dr. Kalyan Kumar Pasunooti

Research Scientist at Singapore-MIT Alliance for Research & Technology Centre

Singapore’

Accomplished Peptide, Protein and Medicinal chemist with 16 years of academic and industrialexperience in the field of drug discovery and development. Specializations: Peptide & Protein Chemistry,Medicinal Chemistry (Drug Discovery and Development) and Chemical Biology.

Research Scientist at Singapore-MIT Alliance for Research and Technology

Research Fellow at Nanyang Technological University, Singapore
Former Post-Doctoral Fellow at Johns Hopkins School of Medicine
Studied Physical organic chemistry at PG College of Science, Saifabad/Osmania University
Studied M.P.C at Government Junior College, Hanamkonda
Studied B.Sc. at Kakatiya Government Degree College
Went to Z. P. S. S. Geesugonda

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ANTHONY MELVIN CRASTO

https://newdrugapprovals.org/

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

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General Pharmacology

Uncategorized Comments Off

Dec 312018

Top 20 General Pharmacology Questions Every one of us Should Know

*Q.1 What is Pharmacology?*

Ans: Pharmacology is a branch of science that deals with the interaction of drugs with living organisms. Or The study of Pharmacokinetics and Pharmacodynamics.

*Q.2 What is a Drug?*

Ans: A drug is any chemical entity that causes a change in biological function in a living organism.some drugs are formed inside the body such as insulin and noradrenaline etc.drugs that are introduced into the body from outside are called Xenobiotics.

*Q.3 What Is a Dose?*

Ans: A Specific Amount of Drug Prescribed to be taken at one time.

*Q.4 What Is Blood Brain Barrier?*

It is A Tight Endothelial Cells Of the Brain Capillaries And Glial Cells Of The Brain Around The blood capillaries that doesn’t allow the passage of certain lipid insoluble substances to pass from the blood into the brain.Lipid Soluble Drugs can easily Cross This Barrier.Examples Of Lipid soluble Drugs are; Diazepam, Thiopental, And Phenobarbitol.

*Q.5 What is Volume Of Distribution?*

Ans: The total Volume Of The Body Fluid in which a drug appears to be distributed according to its concentration in the blood or plasma.VD of a drug can be determined by the following Formula,

VD (Volume OF Distribution) =Total Amount OF Drug In the Body/Concentration of drug in the blood plasma.

*Q.6 What Is Potency?*

Ans: It is the weight of the drug that produces a certain magnitude of response.For Example Lesser the weight of drug required to produce a given effect, more its potency.Also More the weight of the drug required to produce the same effect lesser its potency.e.g Clonidine Produce its antihypertensive effect in 0.2-0.3mg Daily Dose.While Antihypertensive dose of methyldopa is 500-2000mg Per Day.Thus Clonidine IS more Potent than methyldopa.

*Q.7 What Is Efficacy?*

Ans:If the dose of a drug is increased its effect will be increased proportionately, until a stage is reached beyond there is no further increase in effect will occur,even if a large dose of drug is given.thix maximum effect of drug beyond which no further increase in its effect occurs even if the dose of the drug is increased to a large amount is called efficacy or maximal efficacy.example morphine has more efficacy than aspirin as an analgesic .morphine is more effective in the severe type of pains while aspirin is effective in mild to moderate pain.

*Q.8 What is Therapeutic index?*

The ratio between median toxic dose (TD50) and median effective dose (ED50) is called therapeutic index.

Therapeutic index= TD50/ED50

*Q.9 What is idiosyncrasy?*

It is a rare type of response to a drug that is not related to its dose, that is, even a small dose can cause it.For example.A rare adverse effect with chloramphenicol is aplastic anemia.

*Q.10 What is Hypersensitivity?*

An allergic or immunological response to a drug .for example anaphylactic shock with penicillin is a severe type of hypersensitivity reaction.

*Q.11 What is Tolerance?*

Ans: Repeated use of a drug causes a gradual decrease in the response to the drug.e.g chronic use of morphine will decrease many of its effects in the body, therefore the dose of the drug has to be increased with the passage of time to maintain the usual effects of the drug.

*Q.12 What is a Receptor?*

Ans: Receptor is a macromolecule (Big molecule).Most of the receptors are protein in nature.mostly those drugs that act on the cells bind to the receptors.Those drugs which bind to the receptor and show their effect are called agonists.While some drugs bind to the receptor but don’t produce an effect.These drugs are known as an antagonist as they prevent the binding of agonists with the receptors.

*Q.14 What is the adverse drug reaction?*

Drugs may produce two types of effect i.e Useful effects and harmful effects.harmful effects are also known as adverse drug reaction or undesired effects.These effects may range from the mild type of adverse effect to severe effects that may cause a death of the person.

Adverse drug reaction may be classified into the following types;

Idiosyncrasy

Drug allergy

Direct toxic effect

Drug dependence

Tolerance

*Q.15 What is Shock?*

It is a clinical condition in which there is an inadequate supply of blood to tissues.it causes hypotension, oliguria, and metabolic acidosis.Following are the common types of shock:

A. Hypovolemic shock

B. Septic shock

C. Cardiogenic shock

D. Anaphylactic shock

*Q.16 What is Drug Clearance?*

Ans: It Can be defined as Volume Of blood or plasma cleared of the drug in a unit period of time.Thus, to determine clearance we have to find that volume of blood or plasma from which a drug is removed during a unit period of time.By removal of drug we mean metabolism and excretion of drug.if we know the clearance of a drug we can adjust its dose properly.clearance of the drug can be determined by the following formula.

Cl: Rate of elimination/Concentration of drug in the blood

Where is Cl is clearance?

*Q.17 What is Drug Excretion?*

Ans: Removal of drugs from the body is known as their excretion.Drugs are excreted from the body either in the form of their metabolites or in unchanged form.Excretion can occur from the following routes;

A) Faecal

B) Renal

C) Biliary

D)Pulmonary

E)Others like to sweat, saliva, milk etc

*Q.18 What is Toxicology?*

It is an aspect of pharmacology that deals with the adverse effects of drugs on living organisms .in addition to drugs used in therapy, it also deals with many other chemicals that may be responsible for the household, environmental, or industrial intoxication.

*Q.19 What is antidote?*

Ans: Antidotes are Any Substance which Is Used To oppose the effects of poisons without causing any damage to The body. Example antidote for benzodiazepine is flumazenil.

*Q.20 What is Bioavailability?*

It can be defined as a fraction of unmodified drug reaching into the systemic circulation after it is administered by any route.IV administration of drug produces 100% bioavailability as a whole of the drug enters the systemic circulation.Oral administration of the drug may not produce 100% bioavailability due to incomplete absorption of a drug from the Gastrointestinal tract and due to first pass effects of some of the drugs.

[29/12, 10:20 AM] ‪+91 93017 24365‬: *Sun Pharma arm gets relief from US court in patent infringement case*

_The lawsuit alleged trade secret misappropriation and patent infringement of DUSA’s photodynamic therapy patents covering its product._

: Sun Pharma Wednesday said, DUSA Pharmaceuticals, an arm of of the Mumbai based pharma giant, has received relief from a US court in a patent infringement case.

Massachusetts-based DUSA has been granted preliminary injunctive relief by a federal district court prohibiting defendants Biofrontera Inc, Biofrontera Bioscience GmbH, Biofrontera Pharma GmbH, and Biofrontera AGf from using its confidential and proprietary trade secret information, Sun Pharmaceutical Industries said in a regulatory filing.

Earlier this year, DUSA, which is wholly-owned by Sun Pharma, filed a lawsuit against the Biofrontera defendants in the US District Court for the District of Massachusetts.

The lawsuit alleged trade secret misappropriation and patent infringement of DUSA’s photodynamic therapy patents covering its product.

DUSA, in its amended complaint filed in July 2018, additionally alleged the Biofrontera defendants misappropriated confidential and trade secret information by obtaining confidential information from its former employees to sell and market defendants’ own products.

The lawsuit sought an assessment of both damages and injunctive relief against the Biofrontera defendants, Sun Pharma said.

The court’s order prohibits Biofrontera from making use of or disseminating DUSA’s sales and financial information, customer lists and customer target lists, training and marketing materials, standard operating procedures, technical information, and unpublished clinical data, and any derivations thereof, effective immediately, it added.

[29/12, 10:32 AM] ‪+91 93017 24365‬: **CDSCO tightens safety & labelling rules for acne drug isotretinoin, prescription mandatory*The Central Drugs Standard Control Organisation (CDSCO) has tightened safety guidelines and labelling rules for isotretinoin capsules, an oral drug used for the treatment and prevention of severe acne, citing harmful side effects and adverse reactions. The national drug regulator is learnt to have taken the action following complaints received by the Centralised Public Grievance Redress and Monitoring System.

The stricter regulations for manufacture and retail of isotretinoin were recommended by the CDSCO’s Subject Expert Committee for dermatology and allergy at its recent meeting.

Isotretinoin is an oral derivative of vitamin A. According to clinicians, the medication is prescribed to people who have severe and painful acne that affects their quality of life. The average course of treatment is 4-6 months. It is available in India under various brand names such as Zenatane, Isotroin, Retinon, Aktret, Ratino and Isopad. Many users also obtain the product online.

Isotretinoin’s 10mg and 20mg capsules were approved by the CDSCO way back in 2002 for treatment of severe nodular acne that were unresponsive to antibiotic therapy. The nod was given with various conditions including box warning on packs for female patients as the drug may cause severe birth defects.

Making the rules more rigorous, the national regulator has ordered drug controllers of all states and Union Territories to ensure that the medicine is sold on prescription of dermatologists only. Moreover, chemists should maintain details of the sale as per requirements of Drugs & Cosmetics Rules of 1945.

The drug pack should henceforth carry the following *box warning* : *“This medicine may cause severe birth defects; you must not take this medicine if you are pregnant or may likely become pregnant during treatment. You should also avoid pregnancy for 6 months after stopping the treatment”.*

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Orochem Molecular Purification by Design

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Dec 102018

Established in 1996, Orochem Technologies Inc. started as a Biotech and Chromatography company to manufacture unique Sample Prep Technology “Products” for the Bioanalysis, Drug Discovery, and the Genomics and Proteomics markets.

Established in 1996, Orochem Technologies Inc. started as a Biotech and Chromatography company to manufacture unique Sample Prep Technology Products for the Bioanalysis, Drug Discovery, and the Genomics and Proteomics markets. Backed with unique expertise in high throughput formats, membranes and surface chemistries, Orochem was one of the first companies to translate the concept of pre-filters from single to high throughput formats, a concept now widely implemented for sample prep plates in the biotech and analytical markets. In the year 2001 Orochem manufactured the first commercially available Protein Crash and Precipitation 96-well plate for Bioanalytical processes. By the year 2006, with the acquisition of Column Engineering Inc, Orochem evolved to become a “full-service” provider for silica manufacturing utilized for analytical and preparatory chromatography. Orochem invests heavily into R&D in-house and owns strong intellectual property in stationary phases for achiral and Chiral Chromatography.

Orochem’s is globally recognized as an organization that conceives, develops, and installs some of the most technologically viable solutions for “highest purities” for industrial or “metric ton” scale purification for API’s, nutritional supplements, fatty acids, and specialty sugars. Orochem provides Simulated Moving Bed (SMB) Chromatography technology for the laboratory scale, pilot scale and large-scale purification of commercially viable molecules for its customers around the world. Orochem’s products and services for Simulated Moving Bed Chromatography include Synthesis and manufacture of stationary phases “tailored for specific separations”, a uniquely engineered SMB system and the installation and commissioning of the SMB systems at customer sites with well-trained Orochem technical service engineers.

Orochem owns several manufacturing facilities around the world. The Naperville, Illinois, USA site has about 84,000 square feet of manufacturing area where most of the Membrane Filter Plates, Silica manufacturing, Silica bonding, Solid Phase Extraction products and HPLC Columns are manufactured. Orochem India, Mumbai has 20,000 square feet facility and manufactures Sample prep products for the Discovery & Clinical Research organizations in Asia. Simulated Moving Bed chromatography systems are designed, built and assembled completely at our US locations in Naperville in Illinois.

USA (HQ)

Orochem Technologies Inc.
   630 210 8300
   630 210 8315
   info@orochem.com
   340 Shuman Blvd., Naperville, 60563, IL.

Orochem Molecular Purification by Design

https://orochem.com/

Latest artificial glucose-binding receptor is best yet

diabetes, Uncategorized Comments Off

Nov 202018

It’s a receptor that binds glucose strongly and with the highest selectivity yet. Could help with #diabetes treatment: http://ow.ly/EPzn30mDYjf

Read all at

https://cen.acs.org/biological-chemistry/Latest-artificial-glucose-binding-receptor/96/i46?platform=hootsuite

Carbanio – a digital B2B platform to buy and sell Chemicals in India

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Nov 022018

Hello All

I have an exciting news which I want to share today.

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I was surprised to see that there is one stunning B2B Marketplace which is specially meant for ready stock of Chemicals in India.

Carbanio (www.carbanio.com) is showing promising future for all Indian Suppliers which helps them not only buy Chemicals within India, but also to Sell Chemicals. They are no registration charges and no charges to publish Chemical products. Hope they are going to launch internationally very soon which will boost exports from India.

This is really a great news for everyone who would like to generate more revenue by selling online. Online sales will not only help you in increasing revenue, but also will enable you to do business 24*7. In addition, you will also receive new requirements from their Buyers which will help you in scaling your business and portfolio.

To know more about the selling benefits, visit https://www.carbanio.com/sell-on-carbanio

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API, Impurities and Regulatory aspects

regulatory, Uncategorized Comments Off

Oct 242018

The impurities in pharmaceuticals are unwanted chemicals that remain with the active pharmaceutical ingredients (APIs) or develop during formulation or upon aging of both API and formulation. The presence of these unwanted chemicals even in trace amount may influence the efficacy and safety of pharmaceutical product

Impurities is defined as an entity of drug substances or drug product that is not chemical entity defined as drug substances an excipients or other additives to drugproduct.

The control of pharmaceutical impurities is currently a critical issue to the pharmaceutical industry. Structure elucidation of pharmaceutical impurities is an important part of the drug product development process. Impurities can have unwanted pharmacological or toxicological effects that seriously impact product quality and patient safety. Potential sources and mechanisms of impurity formation are discussed for both drugs. The International Conference on Harmonization (ICH) has formulated a workable guideline regarding the control of impurities. In this review, a description of different types and origins of impurities in relation to ICH guidelines and, degradation routes, including specific examples, are presented. The article further discusses measures regarding the control of impurities in pharmaceuticals substance and drug product applications.

Impurities in pharmaceuticals are the unwanted chemicals that remain with the active pharmaceutical ingredients (APIs), or develop during formulation, or upon aging of both API and formulated APIs to medicines. The presence of these unwanted chemicals even in small amounts may influence the efficacy and safety of the pharmaceutical products.

According to ICH, an impurity in a drug substance is defined as-“any component of the new drug substance that is not the chemical entity defined as the new drug substance”. There is an ever increasing interest in impurities present in APIs recently, not only purity profile but also impurity profile has become essential as per various regulatory requirements. The presence of the unwanted chemicals, even in small amount, may influence the efficacy and safety of the pharmaceutical products.

“In the pharmaceutical world, an impurity is considered as any other organic material, besides the drug substance, or ingredients, arise out of synthesis or unwanted chemicals that remains with API’s”

The control of pharmaceutical impurities is currently a critical issue to the pharmaceutical industry. The International Conference on Harmonization (ICH) has formulated a workable guideline regarding the control of impurities.

CLASSIFICATIONS OF IMPURITIES:
Impurities have been named differently or classified as per the ICH guidelines as follows:

A] Common names
1. By-products
2. Degradation products
3. Interaction products
4. Intermediates
5. Penultimate intermediates
6. Related products
7. Transformation products

B] United State Pharmacopeia
The United States Pharmacopoeia (USP) classifies impurities in various sections:
1. Impurities in Official Articles
2. Ordinary Impurities
3. Organic Volatile Impurities

C] ICH Terminology
According to ICH guidelines, impurities in the drug substance produced by chemical synthesis can broadly be classified into following three categories –
1. Organic Impurities (Process and Drug related)
2. Inorganic Impurities
3. Residual Solvents

Organic impurities may arise during the manufacturing process and or storage of the drug substance may be identified or unidentified, volatile or non-volatile, and may include
1. Starting materials or intermediates
2. By-products
3. Degradation products

Impurities are found in API’s unless, a proper care is taken in every step involved throughout the multi-step synthesis for example; in paracetamol bulk, there is a limit test for p-aminophenol, which could be a starting material for one manufacturer or be an intermediate for the others. Impurities can also be formed by degradation of the end product during manufacturing of the bulk drugs.

The degradation of penicillin and cephalosporin are well-known examples of degradation products. The presence of a β-lactam ring as well as that of an a-amino in the C6 or C7 side chain plays a critical role in their degradation.

The primary objectives of process chemical research are the development of efficient, scalable, and safe reproducible synthetic routes to drug candidates within the developmental space and acting as a framework for commercial production in order to meet the requirement of various regulatory agencies. Therefore, assessment and control of the impurities in a drug substance and drug product are important aspects of drug development for the development team to obtain various marketing approvals. It is extremely challenging for an organic chemist to identify the impurities which are formed in very small quantities in a drug substance and wearisome if the product is nonpharmacopeial. A study describes the formation, identification, synthesis, and characterization of impurities found in the preparation of API. A study will help a synthetic organic chemist to understand the potential impurities in API synthesis and thereby obtain the pure compound.

Care to taken ensure that desired drug metabolism, safety and clinical studies are not jeopardized by inconsistent purity or impurities having potential harmful toxicological properties,

As regulatory guidelines promulgated by the International Conference on Harmonization (ICH)(1) dictate rigorous identification of impurities at levels of 0.1%,

It is important to develop commercially viable processes for drug substance manufacture to allow greater and more affordable access in the health care sector. In regard to the process development of drug substances, it is essential to know the origin and method of control of any unwanted substances present in it. The limit should be controlled under the threshold of toxicological concern (TTC) for the purpose of ensuring safety and efficacy of the drug and to meet the requirements of various drug regulatory agencies.(2,3)

The impurities in drug substances mostly come from starting substrates, reagents, solvents, and side reactions of the synthetic route employed. Therefore, assessment and control of the undesired substances is an essential aspect of the drug development journey, with special consideration of patient health risk.(4,5)

The isolation/synthesis and characterization of process-related critical impurities (more difficult to control under the desired regulatory limits) of any drug substance in order to evaluate their origin/fate and thereafter their control strategies in the developed process as per International Council for Harmonisation (ICH) guidelines.(4)

The goal of pharmaceutical development is to develop process understanding and control which will yield procedures that consistently deliver products possessing the desired key quality attributes. To achieve this, the quality by design (QbD) paradigm has been employed in combination with process-risk assessment strategies to systematically gather knowledge through the application of sound scientific approaches.(6)

Ganzer et al. recently published an article about critical process parameters and API synthesis.(7) The article presented an in-depth discussion of a stepwise, process risk assessment approach to facilitate the identification and understanding of critical quality attributes, process parameters, and in-process controls. The primary benefit of working within the QbD conceptual framework and employing process risk assessment strategies is the reproducible delivery of high-quality active pharmaceutical ingredient (API). However, a secondary benefit is the ability to obtain regulatory flexibility with respect to filing requirements.(8)

The control of impurities observed in an API is critical in delivering an API of high quality. Identification and understanding of the mechanism of formation of process-related impurities are critical pieces of information required for the development of control strategies. In addition, to ensure a continuing supply of API for drug product clinical manufacture, timely identification of key impurities is essential. These synthesis-related impurities and their precursors are considered as critical impurities because they directly affect the quality and impurity profile of the API. It is our practice that critical impurities be identified if practicable. Therefore, the timely identification of critical impurities becomes an integral part of process development.

There are different approaches to the identification of impurities. Described, herein, a general strategy that we have used in our laboratory, which leads to the rapid identification of impurities. To identify the structure of a low-level unknown impurity, we usually use liquid chromatography/mass spectrometry (LC/MS)/high-resolution MS (HRMS) and tandem MS (MS/MS) for molecular weight (MW) determination, elemental composition, and fragmentation patterns. On the basis of the mass spectrometric data and knowledge of the process chemistry, one or more possible structure(s) may be assigned for the impurity, with definitive structure information obtained by inspection of the HPLC retention time, UV spectrum, and MS profile of an authentic compound.

If an authentic sample is not available, the isolation of a pure sample of the impurity is undertaken for structure elucidation using NMR spectroscopy. The isolation of low-level impurities is usually conducted using preparative HPLC chromatography

REFERENCES

1 ICH Q3A Impurities in New Drug Substances, R2; International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH): Geneva, Switzerland, October 2006; http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3A_R2/Step4/Q3A_R2__Guideline.pdf.

2. Patil, G. D.; Kshirsagar, S. W.; Shinde, S. B.; Patil, P. S.; Deshpande, M. S.; Chaudhari, A. T.; Sonawane, S. P.; Maikap, G. C.; Gurjar, M. K.Identification, Synthesis, and Strategy For Minimization of Potential Impurities Observed In Raltegravir Potassium Drug Substance. Org. Process Res. Dev. 2012, 16, 1422– 1429, DOI: 10.1021/op300077m
3. Huang, Y.; Ye, Q.; Guo, Z.; Palaniswamy, V. A.; Grosso, J. A. Identification of Critical Process Impurities and Their Impact on Process Research and Development. Org. Process Res. Dev.2008, 12, 632– 636, DOI: 10.1021/op800067v

4. ICH Harmonised Tripartite Guideline Q3A(R): Impurities in New Drug Substances; International Conference on Harmonization: Geneva, 2002.

5. Mishra, B.; Thakur, A.; Mahata, P. P. Pharmaceutical Impurities: A Review. Int. J. Pharm. Chem.2015, 5 (7), 232– 239

6 International Conference on Harmonisation (ICH) Guidelines; Q8, Pharmaceutical Development, 2005; Q9, Quality Risk Management, 2006.

7 Ganzer, W. R.; Materna, J. A.; Mitchell, M. B.; Wall, L. K. Pharm. Technol. 2005, July 2) 1–12.

8 Nasr, M. Drug Information Association Annual Meeting, Philadelphia, PA, June 19, 2006; Pharmaceutical Quality Assessment System (PQAS) in the 21st Century, 2006.

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