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DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

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

 Uncategorized  Comments Off on Kalyan Kumar Pasunooti, Novel Tetrazole-Containing Analogues of Itraconazole as Potent Antiangiogenic Agents with Reduced Cytochrome P450 3A4 Inhibition
Jan 052019
 
Abstract Image

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

Department of Pharmacology and Molecular Sciences and Department of OncologyJohns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
J. Med. Chem.201861 (24), pp 11158–11168
DOI: 10.1021/acs.jmedchem.8b01252
Publication Date (Web): November 27, 2018
Copyright © 2018 American Chemical Society
*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

kp1

str1 str2

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_Pasunooti2

 

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 SocietyOrg. Lett.ACS Chem BioJ 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.

ExperienceSingapore-MIT Alliance for Research & Technology Centre

Research Scientist

  • Company NameSingapore-MIT Alliance for Research & Technology Centre

    Dates EmployedJul 2017 – Present

    Employment Duration1 yr 4 mos

    LocationSingapore

    Medicinal Chemistry and Drug Discovery

  • Research Fellow

    Company NameNanyang Technological University, Singapore

    Dates EmployedOct 2013 – Jun 2017

    Employment Duration3 yrs 9 mos

    LocationSingapore

    Peptide & Protein Chemistry and Medicinal Chemistry

  • Postdoctoral Fellow

    Company NameJohns Hopkins Medicine

    Dates EmployedMay 2012 – Sep 2013

    Employment Duration1 yr 5 mos

    LocationBaltimore, Maryland Area

    Medicinal chemistry, Drug Discovery, Pharmacology and Chemical Biology

  • Postdoctoral Associate

    Company NameNanyang Technological University

    Dates EmployedJul 2011 – Mar 2012

    Employment Duration9 mos

    LocationSingapore

    Organic synthesis, Peptide & Carbohydrate chemistry and Medicinal chemistry.

  • Senior Research Associate in Medicinal Chemistry

    Company NameGVK Biosciences

    Dates EmployedJan 2007 – Jul 2007

    Employment Duration7 mos

    LocationHyderabad Area, India

    Synthesis of bioactive molecules for medicinal chemistry applications.

  • Junior Scientist in Medicinal Chemistry (Anti-Infective group)

    Company NameDr. Reddy’s Laboratories

    Dates EmployedAug 2003 – Dec 2006

    Employment Duration3 yrs 5 mos

    LocationHyderabad Area, India

    Medicinal chemistry (Anti-Infective group): My work entails design and synthesis of newoxazolidinone derivatives and new chemical entities as novel antibacterial agents. As a researchscientist my job demanded me to carry out extensive literature survey to design possible syntheticroutes for a proposed molecule and to carry out the total synthetic part in the laborator… See more

  • Education

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    General Pharmacology

     Uncategorized  Comments Off on General Pharmacology
    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

     Uncategorized  Comments Off on Orochem Molecular Purification by Design
    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/

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    Latest artificial glucose-binding receptor is best yet

     diabetes, Uncategorized  Comments Off on Latest artificial glucose-binding receptor is best yet
    Nov 202018
     

    09646-leadcon-structure.jpg

    It’s a receptor that binds glucose strongly and with the highest selectivity yet. Could help with treatment:

    Read all at

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

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

     Uncategorized  Comments Off on Carbanio – a digital B2B platform to buy and sell Chemicals in India
    Nov 022018
     

     

    car1 car2Hello All

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

    Couple of days ago, I was browsing on the internet to see if we can buy ready stock of Chemicals online, especially from Indian Suppliers.

    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

    Those who wish to buy, the biggest benefit of this platform is you can buy ready stock and get it delivered at your doorstep with assured Purity and Quality. I see there are huge discounts offered by their registered Sellers, which will be a cost benefit factor.

    Another plus point in this site is, you can post your Chemical requirements in case if that is not available on the platform, they will help you in sourcing it for you!
    carbanio gif (1)
    To know more about the buying benefits, visit https://www.carbanio.com/buyer

    For free registration, please visit https://www.carbanio.com/register

    In case if you still want to know more, you can get in touch with them via businesssupport@carbanio.com

    Md. Ayesha Parveen  (CEO at Carbanio)
    see article on linkedin

    Ayesha MD

    CEO@Carbanio
    Email

    Ayesha MD

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    API, Impurities and Regulatory aspects

     regulatory, Uncategorized  Comments Off on API, Impurities and Regulatory aspects
    Oct 242018
     
    Image result for impurities
    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, R2International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)Geneva, Switzerland, October 2006http://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 SubstanceOrg. Process Res. Dev. 2012161422– 1429DOI: 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 DevelopmentOrg. Process Res. Dev.200812632– 636DOI: 10.1021/op800067v

    4. ICH Harmonised Tripartite Guideline Q3A(R): Impurities in New Drug SubstancesInternational Conference on HarmonizationGeneva2002.

    5. Mishra, B.Thakur, A.Mahata, P. P. Pharmaceutical Impurities: A ReviewInt. J. Pharm. Chem.20155 (7), 232– 239

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

    GanzerW. R.MaternaJ. A.MitchellM. B.WallL. K. Pharm. Technol. 2005July 21–12.

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

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    Kalyan Kumar Pasunooti, 5-Methylisoxazole-3-carboxamide-Directed Palladium-Catalyzed γ-C(sp3)–H Acetoxylation and Application to the Synthesis of γ-Mercapto Amino Acids for Native Chemical Ligation

     Uncategorized  Comments Off on Kalyan Kumar Pasunooti, 5-Methylisoxazole-3-carboxamide-Directed Palladium-Catalyzed γ-C(sp3)–H Acetoxylation and Application to the Synthesis of γ-Mercapto Amino Acids for Native Chemical Ligation
    Oct 132018
     
    Abstract Image

    Palladium-catalyzed acetoxylation of the primary γ-C(sp3)–H bonds in the amino acids Val, Thr, and Ile was achieved using a newly discovered 5-methylisoxazole-3-carboxamide directing group. The γ-acetoxylated α-amino acid derivatives could be easily converted to γ-mercapto amino acids, which are useful for native chemical ligation (NCL). The first application of NCL at isoleucine in the semisynthesis of a Xenopus histone H3 protein was also demonstrated.

    5-Methylisoxazole-3-carboxamide-Directed Palladium-Catalyzed γ-C(sp3)–H Acetoxylation and Application to the Synthesis of γ-Mercapto Amino Acids for Native Chemical Ligation

    School of Biological Sciences, Nanyang Technological UniversitySingapore 637551
    Org. Lett.201618 (11), pp 2696–2699
    DOI: 10.1021/acs.orglett.6b01160
    Publication Date (Web): May 24, 2016
    Copyright © 2016 American Chemical Society
    *E-mail: cfliu@ntu.edu.sg.

    link

    https://pubs.acs.org/doi/abs/10.1021/acs.orglett.6b01160

    hps://pubs.acs.org/doi/suppl/10.1021/acs.orgletttt.6b01160/suppl_file/ol6b01160_si_001.pdf

    str3 str1 str2

     

    Kalyan_Pasunooti2

     

    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.

    ExperienceSingapore-MIT Alliance for Research & Technology Centre

    Research Scientist

  • Company NameSingapore-MIT Alliance for Research & Technology Centre

    Dates EmployedJul 2017 – Present

    Employment Duration1 yr 4 mos

    LocationSingapore

    Medicinal Chemistry and Drug Discovery

  • Research Fellow

    Company NameNanyang Technological University, Singapore

    Dates EmployedOct 2013 – Jun 2017

    Employment Duration3 yrs 9 mos

    LocationSingapore

    Peptide & Protein Chemistry and Medicinal Chemistry

  • Postdoctoral Fellow

    Company NameJohns Hopkins Medicine

    Dates EmployedMay 2012 – Sep 2013

    Employment Duration1 yr 5 mos

    LocationBaltimore, Maryland Area

    Medicinal chemistry, Drug Discovery, Pharmacology and Chemical Biology

  • Postdoctoral Associate

    Company NameNanyang Technological University

    Dates EmployedJul 2011 – Mar 2012

    Employment Duration9 mos

    LocationSingapore

    Organic synthesis, Peptide & Carbohydrate chemistry and Medicinal chemistry.

  • Senior Research Associate in Medicinal Chemistry

    Company NameGVK Biosciences

    Dates EmployedJan 2007 – Jul 2007

    Employment Duration7 mos

    LocationHyderabad Area, India

    Synthesis of bioactive molecules for medicinal chemistry applications.

  • Junior Scientist in Medicinal Chemistry (Anti-Infective group)

    Company NameDr. Reddy’s Laboratories

    Dates EmployedAug 2003 – Dec 2006

    Employment Duration3 yrs 5 mos

    LocationHyderabad Area, India

    Medicinal chemistry (Anti-Infective group): My work entails design and synthesis of newoxazolidinone derivatives and new chemical entities as novel antibacterial agents. As a researchscientist my job demanded me to carry out extensive literature survey to design possible syntheticroutes for a proposed molecule and to carry out the total synthetic part in the laborator… See more

  • Education

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    4-(2-fluoro-4-nitrophenyl)morpholine

     Uncategorized  Comments Off on 4-(2-fluoro-4-nitrophenyl)morpholine
    Sep 202018
     

    str3 str4

    4-(2-fluoro-4-nitrophenyl)morpholine

    1H NMR (400MHz, CDCl3)  8.03 (ddd J=1.0, 2.6 and 9.0Hz, 1H, ArH), 7.94 (dd J=2.6 and 13.1Hz, 1H, ArH), 6.94 (t J=8.7Hz, 1H, ArH), 3.90 (t J=4.7Hz, 4H, 2xCH2O), 3.31 (m, 4H, 2xCH2N).

    13C NMR (100MHz, CDCl3)  153.3 (d J=249.5), 145.6 (d J=7.8Hz), 121.1 (d J=3.0Hz), 117.0 (d J=3.9Hz), 112.7 (d J=6.4Hz), 66.7, 50.0 (d J=4.9Hz).

    HRMS [M] Calcd for C10H11FN2O3 226.0748, Found 226.0749.

     

    Catalytic Static Mixers for the Continuous Flow Hydrogenation of a Key Intermediate of Linezolid (Zyvox)

    James GardinerXuan NguyenCharlotte GenetMike D. HorneChristian H. Hornung, and John Tsanaktsidis

    Org. Process Res. Dev., Article ASAP

    DOI: 10.1021/acs.oprd.8b00153

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    3-fluoro-4- morpholinoaniline

     Uncategorized  Comments Off on 3-fluoro-4- morpholinoaniline
    Sep 202018
     

    STR1 STR2

    3-fluoro-4- morpholinoaniline
    1H NMR (400MHz, CDCl3)  6.82 (m, 1H, ArH), 6.43 (m, 2H, 2xArH), 3.87 (m, 4H, 2xCH2O), 3.58 (brs, 2H, NH2), 2.99 (m, 4H, 2xCH2N). 13C NMR (100MHz, CDCl3)  156.9 (d J= 245.4Hz), 143.0 (d J=10.4Hz), 131.8 (d J=9.7Hz), 120.4 (d J=4.2Hz), 110.8 (d J=3.0Hz), 104.0 (d J=23.8Hz), 67.3, 51.9 (d J=2.1Hz). HRMS [M] Calcd for C10H13FN2O 196.1006, Found 196.1004.
    Org. Process Res. Dev., Article ASAP
    DOI: 10.1021/acs.oprd.8b00153

     

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    Crystallization

     Uncategorized  Comments Off on Crystallization
    Sep 122018
     

    Image result for Crystallization

    Crystallization is the (natural or artificial) process by which a solid forms, where the atoms or molecules are highly organized into a structure known as a crystal. Some of the ways by which crystals form are precipitating from a solutionfreezing, or more rarely depositiondirectly from a gas. Attributes of the resulting crystal depend largely on factors such as temperature, air pressure, and in the case of liquid crystals, time of fluid evaporation.

    Crystallization occurs in two major steps. The first is nucleation, the appearance of a crystalline phase from either a supercooled liquid or a supersaturated solvent. The second step is known as crystal growth, which is the increase in the size of particles and leads to a crystal state. An important feature of this step is that loose particles form layers at the crystal’s surface lodge themselves into open inconsistencies such as pores, cracks, etc.

    The majority of minerals and organic molecules crystallize easily, and the resulting crystals are generally of good quality, i.e. without visible defects. However, larger biochemical particles, like proteins, are often difficult to crystallize. The ease with which molecules will crystallize strongly depends on the intensity of either atomic forces (in the case of mineral substances), intermolecular forces (organic and biochemical substances) or intramolecular forces (biochemical substances).

    Crystallization is also a chemical solid–liquid separation technique, in which mass transfer of a solute from the liquid solution to a pure solid crystalline phase occurs. In chemical engineering, crystallization occurs in a crystallizer. Crystallization is therefore related to precipitation, although the result is not amorphous or disordered, but a crystal.

    The design of a successful crystallization process depends on choosing process parameters that will produce crystals of the required purity and yield, that can be isolated, filtered, and dried easily. Process parameters such as cooling rate, solvent composition, and agitation rate directly impact crystallization behavior. Scientists are tasked with understanding how these parameters will influence the outcome of the crystallization process. Often, process parameters for crystallization are chosen based on previous experience, and the outcome is determined by careful analysis of offline analytical data, such as particle size analysis, XRPD, or microscopy. This approach is common, but neglects to consider that crystallization occurs through a sequence of interdependent mechanisms which all contribute to the final outcome, and are each uniquely influenced by the choice of process parameters.

    Crystal nucleation and growth, phase separation, breakage, agglomeration, and polymorph transformations can occur separately, but also simultaneously, and are influenced by process parameters in unique ways. This convolution of mechanisms can mask the true role process parameters play in determining the outcome of a crystallization process, and make crystallization process design a particular challenge for scientists. In the absence of mechanistic understanding for crystallization processes, scientists must often rely on trial-and-error to adjust process parameters and optimize yield, purity, and particle size. This can be a time-consuming task and is one that rarely delivers crystals that can be isolated, filtered, and dried in a facile manner.

    In this series of articles, the most common crystallization mechanisms are described alongside strategies to optimize them. The complete guide to crystallization mechanisms can be downloaded here.

    What is Nucleation?

    Nucleation occurs when solute molecules assemble in a supersaturated solution and reach a critical size. Primary nucleation occurs when nuclei appear from a solution directly and secondary nucleation occurs when nulcei appear in the presence of solids. Nucleation is important to understand because the number and size of nuclei formed can have a dominant influence on the final outcome of the crystallization process. High nucleation rates can lead to excessive fines and a bimodal crystal population which can make product isolation, filtration, and further processing difficult.

    Considerations for Control

    The nucleation rate is dependent on the molecule being crystallized but can be manipulated by considering the solvent type, controlling the supersaturation level, and evaluating the role of impurities and mixing during crystallization design. Seeding is a common strategy deployed to control primary nucleation. Effective seeding can initiate nucleation at a consistent point, and by choosing the seed size and seed loading the nucleation rate can be controlled.

    Secondary nucleation often occurs during a crystallization process when supersaturation increases above a critical limit. This can occur when cooling is too fast or when anti-solvent is added quickly in an effort to increase yield. Secondary nucleation is particularly critical to understand and control because it can suddenly appear during scale-up when process parameters are controlled with less precision compared to the lab

    Key Crystallization Definitions

    Crystallization
    Crystallization is a process whereby solid crystals are formed from another phase, typically a liquid solution or melt.

    Crystal
    Crystal is a solid particle in which the constituent molecules, atoms, or ions are arranged in some fixed and rigid, repeating three-dimensional pattern or lattice.

    Precipitation
    Precipitation is another word for crystallization but is most often used when crystallization occurs very quickly through a chemical reaction.

    Solubility
    Solubility is a measure of the amount of solute that can be dissolved in a given solvent at a given temperature

    Saturated Solution
    At a given temperature, there is a maximum amount of solute that can be dissolved in the solvent. At this point the solution is saturated. The quantity of solute dissolved at this point is the solubility.

    Supersaturation
    Supersaturation is the difference between the actual solute concentration and the equilibrium solute concentration at a given temperature.

    Crystallization
    Process-of-Crystallization-200px.png
    Concepts
    Crystallization · Crystal growth
    Recrystallization · Seed crystal
    Protocrystalline · Single crystal
    Methods and technology
    Boules
    Bridgman–Stockbarger technique
    Crystal bar process
    Czochralski process
    Epitaxy
    Flux method
    Fractional crystallization
    Fractional freezing
    Hydrothermal synthesis
    Kyropoulos process
    Laser-heated pedestal growth
    Micro-pulling-down
    Shaping processes in crystal growth
    Skull crucible
    Verneuil process
    Zone melting
    Fundamentals
    Nucleation · Crystal
    Crystal structure · Solid

    Busting a myth about mechanochemical crystallization

    Adding varying amounts of liquid yields multiple crystal forms
    Chart and structures showing the different phases of caffeine and anthranilic acid cocrystals that are produced when different amounts of ethanol are added.
    Credit: Cryst. Growth Des.

    [+]Enlarge

    Chart and structures showing the different phases of caffeine and anthranilic acid cocrystals that are produced when different amounts of ethanol are added.
    Mechanochemical crystallization of caffeine and anthranilic acid yields polymorph I, polymorph II, or a mixture, depending on the amount of ethanol added.
    Credit: Cryst. Growth Des.

    Although it may seem counterintuitive to put a compound into a ball mill to turn it into a crystalline form, the approach nonetheless works—and adding varying amounts of liquid can determine the crystal form that results, reports a team led by Bill Jones of the University of Cambridge (Cryst. Growth Des.2016, DOI: 10.1021/acs.cgd.6b00682).

    Compounds of interest for materials and pharmaceuticals applications often crystallize into different forms, called polymorphs. Because polymorphs can have varying stability, solubility, and other properties, forming a specific polymorph can be critically important.

    Chemists have long thought that using one particular liquid when crystallizing compounds via mechanochemical milling always yields one particular polymorph. Seeking to test that dogma, Jones and coworkers crystallized 200 mg of a 1:1 equimolar mixture of caffeine and anthranilic acid using a ball mill, adding from 10 to 100 μL of 15 different liquids.

    Four liquids—acetonitrile, nitromethane, ethylene glycol, and 1,6-hexanediol—formed one polymorph each, regardless of the amount of liquid. The rest of the liquids yielded different polymorphs or mixtures, depending on liquid volume: 10 to 20 μL of ethanol formed polymorph II, for example, whereas 40 to 60 μL formed polymorph I. Additionally, 10 μL of 1-hexanol, 1-octanol, or 1-dodecanol formed polymorph III, a polymorph previously only prepared by desolvation.

    Similar effects could occur for single-component crystals, the authors say. The mechanism behind the phenomenon remains to be determined; the authors suggest that it could be a result of thermodynamic stabilization of nanoparticles, different growth mechanisms of the polymorphs, or changes in the free-energy difference between polymorphs caused by milling conditions.

    See also

    References

    1. Jump up^ Lin, Yibin (2008). “An Extensive Study of Protein Phase Diagram Modification:Increasing Macromolecular Crystallizability by Temperature Screening”. Crystal Growth & Design8 (12): 4277. doi:10.1021/cg800698p.
    2. Jump up^ Chayen, Blow (1992). “Microbatch crystallization under oil — a new technique allowing many small-volume crystallization trials”. Journal of Crystal Growth122 (1-4): 176-180. Bibcode:1992JCrGr.122..176Cdoi:10.1016/0022-0248(92)90241-A.
    3. Jump up^ Benvenuti, Mangani (2007). “Crystallization of soluble proteins in vapor diffusion for x-ray crystallography”. Nature Protocols2: 1663. doi:10.1038/nprot.2007.198.
    4. Jump up to:a b Tavare, N. S. (1995). Industrial Crystallization. Plenum Press, New York.
    5. Jump up to:a b McCabe & Smith (2000). Unit Operations of Chemical Engineering. McGraw-Hill, New York.
    6. Jump up^ “Crystallization”www.reciprocalnet.orgArchived from the original on 2016-11-27. Retrieved 2017-01-03.
    7. Jump up^ “Submerge Circulating Crystallizers – Thermal Kinetics Engineering, PLLC”Thermal Kinetics Engineering, PLLC. Retrieved 2017-01-03.
    8. Jump up^ “Draft Tube Baffle (DTB) Crystallizer – Swenson Technology”Swenson TechnologyArchived from the original on 2016-09-25. Retrieved 2017-01-03.

    Further reading

    • A. Mersmann, Crystallization Technology Handbook (2001) CRC; 2nd ed. ISBN0-8247-0528-9
    • Tine Arkenbout-de Vroome, Melt Crystallization Technology (1995) CRC ISBN1-56676-181-6
    • “Small Molecule Crystallization” (PDF) at Illinois Institute of Technology website
    • Glynn P.D. and Reardon E.J. (1990) “Solid-solution aqueous-solution equilibria: thermodynamic theory and representation”. Amer. J. Sci. 290, 164–201.
    • Geankoplis, C.J. (2003) “Transport Processes and Separation Process Principles”. 4th Ed. Prentice-Hall Inc.
    • S.J. Jancic, P.A.M. Grootscholten: “Industrial Crystallization”, Textbook, Delft University Press and Reidel Publishing Company, Delft, The Netherlands, 1984.

    External links

    Crystallization Publications

    Discover a selection of crystallization publications below:

    The seminal study on the nucleation of crystals from solution
    Jaroslav Nývlt, Kinetics of nucleation in solutions, Journal of Crystal Growth, Volumes 3–4, 1968.

    Excellent study on how crystals grow form solution
    Crystal Growth Kinetics, Material Science and Engineering, Volume 65, Issue 1, July 1984.

    An excellent description of the reasons solute-solvent systems exhibit oiling out instead of crystallization
    Kiesow et al., Experimental investigation of oiling out during crystallization process, Journal of Crystal Growth, Volume 310, Issue 18, 2008.

    Detailed examination of why agglomeration occurs during crystallization
    Brunsteiner et al., Toward a Molecular Understanding of Crystal Agglomeration, Crystal Growth & Design, 2005, 5 (1), pp 3–16.

    A study of breakage mechanisms during crystallization
    Fasoli & Conti, Crystal breakage in a mixed suspension crystallizer, Volume 8, Issue8, 1973, Pages 931-946.

    A great overview of how to design effective crystallization processes in the high value chemicals industry
    Paul et al., Organic Crystallization Processes, Powder Technology, Volume 150, Issue 2, 2005.

    Techniques to ensure the correct polymorph is crystallized every time
    Kitamura, Strategies for Control of Crystallization of Polymorphs, CrystEngComm, 2009,11, 949-964.

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