AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Pharmaceutical Manufacturing Encyclopedia, 3rd Edition

 MANUFACTURING  Comments Off on Pharmaceutical Manufacturing Encyclopedia, 3rd Edition
Aug 072016
 

Pharmaceutical Manufacturing Encyclopedia, 3rd Edition by Elsevier Books Reference on Scribd

DESCRIPTION

This industry standard encyclopedia on pharmaceutical manufacturing processes has been completely updated to include FDA drugs approved up to the summer of 2004. The encyclopedia gives details for the manufacture of 2226 pharmaceuticals that are being marketed as a trade-named product somewhere in the world. Each entry includes:

ò Therapeutic function
ò Chemical and common name
ò Structural Formula
ò Chemical Abstracts Registry no.
ò Trade name, manufacturer, country, and year introduced
ò Raw Materials
ò Manufacturing Process

In addition, references are also cited under each drug’s entry to major pharmaceutical works where additional information can be obtained on synthesis and the pharmacology of the individual products.

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Sreeni Labs Private Limited, Hyderabad, India ready to deliver New, Economical, Scalable Routes to your advanced intermediates & API’s in early Clinical Drug Development Stages

 companies, INDIA, MANUFACTURING, new drugs, PRECLINICAL, PROCESS, regulatory  Comments Off on Sreeni Labs Private Limited, Hyderabad, India ready to deliver New, Economical, Scalable Routes to your advanced intermediates & API’s in early Clinical Drug Development Stages
Jul 162016
 

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Sreeni Labs Private Limited, Hyderabad, India is ready to take up challenging synthesis projects from your preclinical and clinical development and supply from few grams to multi-kilo quantities. Sreeni Labs has proven route scouting ability  to  design and develop innovative, cost effective, scalable routes by using readily available and inexpensive starting materials. The selected route will be further developed into a robust process and demonstrate on kilo gram scale and produce 100’s of kilos of in a relatively short time.

Accelerate your early development at competitive price by taking your route selection, process development and material supply challenges (gram scale to kilogram scale) to Sreeni Labs…………

INTRODUCTION

Sreeni Labs based in Hyderabad, India is working with various global customers and solving variety of challenging synthesis problems. Their customer base ranges from USA, Canada, India and Europe. Sreeni labs Managing Director, Dr. Sreenivasa Reddy Mundla has worked at Procter & Gamble Pharmaceuticals and Eli Lilly based in USA.

The main strength of Sreeni Labs is in the design, development of innovative and highly economical synthetic routes and development of a selected route into a robust process followed by production of quality product from 100 grams to 100s of kg scale. Sreeni Labs main motto is adding value in everything they do.

They have helped number of customers from virtual biotech, big pharma, specialty chemicals, catalog companies, and academic researchers and drug developers, solar energy researchers at universities and institutions by successfully developing highly economical and simple chemistry routes to number of products that were made either by very lengthy synthetic routes or  by using highly dangerous reagents and Suzuki coupling steps. They are able to supply materials from gram scale to multi kilo scale in a relatively short time by developing very short and efficient synthetic routes to a number of advanced intermediates, specialty chemicals, APIs and reference compounds. They also helped customers by drastically reducing number of steps, telescoping few steps into a single pot. For some projects, Sreeni Labs was able to develop simple chemistry and avoided use of palladium & expensive ligands. They always begin the project with end in the mind and design simple chemistry and also use readily available or easy to prepare starting materials in their design of synthetic routes

Over the years, Sreeni labs has successfully made a variety of products ranging from few mg to several kilogram scale. Sreeni labs has plenty of experience in making small select libraries of compounds, carbocyclic compounds like complex terpenoids, retinal derivatives, alkaloids, and heterocyclic compounds like multi substituted beta carbolines, pyridines, quinolines, quinolones, imidazoles, aminoimidazoles, quinoxalines, indoles, benzimidazoles, thiazoles, oxazoles, isoxazoles, carbazoles, benzothiazoles, azapines, benzazpines, natural and unnatural aminoacids, tetrapeptides, substituted oligomers of thiophenes and fused thiophenes, RAFT reagents, isocyanates, variety of ligands,  heteroaryl, biaryl, triaryl compounds, process impurities and metabolites.

Sreeni Labs is Looking for any potential opportunities where people need development of cost effective scalable routes followed by quick scale up to produce quality products in the pharmaceutical & specialty chemicals area. They can also take up custom synthesis and scale up of medchem analogues and building blocks.  They have flexible business model that will be in sink with customers. One can test their abilities & capabilities by giving couple of PO based (fee for service) projects.

Some of the compounds prepared by Sreeni labs;

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See presentation below

LINK ON SLIDESHARE

Managing Director at Sreeni Labs Private Limited

 

Few Case Studies : Source SEEENI LABS

QUOTE………….

One virtual biotech company customer from USA, through a common friend approached Sreeni Labs and told that they are buying a tetrapeptide from Bachem on mg scale at a very high price and requested us to see if we can make 5g. We accepted the challenge and developed solution phase chemistry and delivered 6g and also the process procedures in 10 weeks time. The customer told that they are using same procedures with very minor modifications and produced the tetrapeptide ip to 100kg scale as the molecule is in Phase III.

 

One East coast customer in our first meeting told that they are working with 4 CROs of which two are in India and two are in China and politely asked why they should work with Sreeni Labs. We told that give us a project where your CROs failed to deliver and we will give a quote and work on it. You pay us only if we deliver and you satisfy with the data. They immediately gave us a project to make 1.5g and we delivered 2g product in 9 weeks. After receiving product and the data, the customer was extremely happy as their previous CRO couldn’t deliver even a milligram in four months with 3 FTEs.

 

One Midwest biotech company was struggling to remove palladium from final API as they were doing a Suzuki coupling with a very expensive aryl pinacol borane and bromo pyridine derivative with an expensive ligand and relatively large amount of palldium acetate. The cost of final step catalyst, ligand and the palladium scavenging resin were making the project not viable even though the product is generating excellent data in the clinic. At this point we signed an FTE agreement with them and in four months time, we were able to design and develop a non suzuki route based on acid base chemistry and made 15g of API and compared the analytical data and purity with the Suzuki route API. This solved all three problems and the customer was very pleased with the outcome.

 

One big pharma customer from east coast, wrote a structure of chemical intermediate on a paper napkin in our first meeting and asked us to see if we can make it. We told that we can make it and in less than 3 weeks time we made a gram sample and shared the analytical data. The customer was very pleased and asked us to make 500g. We delivered in 4 weeks and in the next three months we supplied 25kg of the same product.

 

Through a common friend reference, a European customer from a an academic institute, sent us an email requesting us to quote for 20mg of a compound with compound number mentioned in J. med. chem. paper. It is a polycyclic compound with four contiguous stereogenic centers.  We gave a quote and delivered 35 mg of product with full analytical data which was more pure than the published in literature. Later on we made 8g and 6g of the same product.

 

One West coast customer approached us through a common friend’s reference and told that they need to improve the chemistry of an advanced intermediate for their next campaign. At that time they are planning to make 15kg of that intermediate and purchased 50kg of starting raw material for $250,000. They also put five FTEs at a CRO  for 5 months to optimize the remaining 5 steps wherein they are using LAH, Sodium azide,  palladium catalyst and a column chromatography. We requested the customer not to purchase the 50kg raw material, and offered that we will make the 15kg for the price of raw material through a new route  in less than three months time. You pay us only after we deliver 15 kg material. The customer didn’t want to take a chance with their timeline as they didn’t work with us before but requested us to develop the chemistry. In 7 weeks time, we developed a very simple four step route for their advanced intermediate and made 50g. We used very inexpensive and readily available starting material. Our route gave three solid intermediates and completely eliminated chromatographic purifications.

 

One of my former colleague introduced an academic group in midwest and brought us a medchem project requiring synthesis of 65 challenging polyene compounds on 100mg scale. We designed synthetic routes and successfully prepared 60 compounds in a 15 month time.  

UNQUOTE…………

 

The man behind Seeni labs is Dr.Sreenivasa  Reddy Mundla

Sreenivasa Reddy

Dr. Sreenivasa Reddy Mundla

Managing Director at Sreeni Labs Private Limited

Sreeni Labs Private Limited

Road No:12, Plot No:24,25,26

  • IDA, Nacharam
    Hyderabad, 500076
    Telangana State, India

Links

LINKEDIN https://in.linkedin.com/in/sreenivasa-reddy-10b5876

FACEBOOK https://www.facebook.com/sreenivasa.mundla

RESEARCHGATE https://www.researchgate.net/profile/Sreenivasa_Mundla/info

EMAIL mundlasr@hotmail.com,  Info@sreenilabs.com, Sreeni@sreenilabs.com

Dr. Sreenivasa Mundla Reddy

Dr. M. Sreenivasa Reddy obtained Ph.D from University of Hyderabad under the direction Prof Professor Goverdhan Mehta in 1992. From 1992-1994, he was a post doctoral fellow at University of Wisconsin in Professor Jame Cook’s lab. From 1994 to 2000,  worked at Chemical process R&D at Procter & Gamble Pharmaceuticals (P&G). From 2001 to 2007 worked at Global Chemical Process R&D at Eli Lilly and Company in Indianapolis. 

In 2007  resigned to his  job and founded Sreeni Labs based in Hyderabad, Telangana, India  and started working with various global customers and solving various challenging synthesis problems. 
The main strength of Sreeni Labs is in the design, development of a novel chemical route and its development into a robust process followed by production of quality product from 100 grams to 100’s of kg scale.
 

They have helped number of customers by successfully developing highly economical simple chemistry routes to number of products that were made by Suzuki coupling. they are able to shorten the route by drastically reducing number of steps, avoiding use of palladium & expensive ligands. they always use readily available or easy to prepare starting materials in their design of synthetic routes.

Sreeni Labs is Looking for any potential opportunities where people need development of cost effective scalable routes followed by quick scale up to produce quality products in the pharmaceutical & specialty chemicals area. They have flexible business model that will be in sink with customers. One can test their abilities & capabilities by giving PO based projects

Experience

Founder & Managing Director

Sreeni Labs Private Limited

August 2007 – Present (8 years 11 months)

Sreeni Labs Profile

Sreeni Labs Profile

View On SlideShare

Principal Research Scientist

Eli Lilly and Company

March 2001 – August 2007 (6 years 6 months)

Senior Research Scientist

Procter & Gamble

July 1994 – February 2001 (6 years 8 months)

Education

University of Hyderabad

Doctor of Philosophy (Ph.D.), 
1986 – 1992

 

PUBLICATIONS

Article: Expansion of First-in-Class Drug Candidates That Sequester Toxic All-Trans-Retinal and Prevent Light-Induced Retinal Degeneration

Jianye Zhang · Zhiqian Dong · Sreenivasa Reddy Mundla · X Eric Hu · William Seibel ·Ruben Papoian · Krzysztof Palczewski · Marcin Golczak

Article: ChemInform Abstract: Regioselective Synthesis of 4Halo ortho-Dinitrobenzene Derivative

Sreenivasa Mundla

Aug 2010 · ChemInform

Article: Optimization of a Dihydropyrrolopyrazole Series of Transforming Growth Factor-β Type I Receptor Kinase Domain Inhibitors: Discovery of an Orally Bioavailable Transforming Growth Factor-β Receptor Type I Inhibitor as Antitumor Agent

Hong-yu Li · William T. McMillen · Charles R. Heap · Denis J. McCann · Lei Yan · Robert M. Campbell · Sreenivasa R. Mundla · Chi-Hsin R. King · Elizabeth A. Dierks · Bryan D. Anderson · Karen S. Britt · Karen L. Huss

Apr 2008 · Journal of Medicinal Chemistry

Article: ChemInform Abstract: A Concise Synthesis of Quinazolinone TGF-β RI Inhibitor Through One-Pot Three-Component Suzuki—Miyaura/Etherification and Imidate—Amide Rearrangement Reactions

Hong-yu Li · Yan Wang · William T. McMillen · Arindam Chatterjee · John E. Toth ·Sreenivasa R. Mundla · Matthew Voss · Robert D. Boyer · J. Scott Sawyer

Feb 2008 · ChemInform

Article: ChemInform Abstract: A Concise Synthesis of Quinazolinone TGF-β RI Inhibitor Through One-Pot Three-Component Suzuki—Miyaura/Etherification and Imidate—Amide Rearrangement Reactions

Hong-yu Li · Yan Wang · William T. McMillen · Arindam Chatterjee · John E. Toth ·Sreenivasa R. Mundla · Matthew Voss · Robert D. Boyer · J. Scott Sawyer

Nov 2007 · Tetrahedron

Article: Dihydropyrrolopyrazole Transforming Growth Factor-β Type I Receptor Kinase Domain Inhibitors: A Novel Benzimidazole Series with Selectivity versus Transforming Growth Factor-β Type II Receptor Kinase and Mixed Lineage Kinase-7

Hong-yu Li · Yan Wang · Charles R Heap · Chi-Hsin R King · Sreenivasa R Mundla · Matthew Voss · David K Clawson · Lei Yan · Robert M Campbell · Bryan D Anderson · Jill R Wagner ·Karen Britt · Ku X Lu · William T McMillen · Jonathan M Yingling

Apr 2006 · Journal of Medicinal Chemistry

Read full-textSource

Article: Studies on the Rh and Ir mediated tandem Pauson–Khand reaction. A new entry into the dicyclopenta[ a, d]cyclooctene ring system

Hui Cao · Sreenivasa R. Mundla · James M. Cook

Aug 2003 · Tetrahedron Letters

Article: ChemInform Abstract: A New Method for the Synthesis of 2,6-Dinitro and 2Halo6-nitrostyrenes

Sreenivasa R. Mundla

Nov 2000 · ChemInform

Article: ChemInform Abstract: A Novel Method for the Efficient Synthesis of 2-Arylamino-2-imidazolines

Read at

[LINK]

Patents by Inventor Dr. Sreenivasa Reddy Mundla

  • Patent number: 7872020

    Abstract: The present invention provides crystalline 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro -4H-pyrrolo[1,2-b]pyrazole monohydrate.

    Type: Grant

    Filed: June 29, 2006

    Date of Patent: January 18, 2011

    Assignee: Eli Lilly and Company

    Inventor: Sreenivasa Reddy Mundla

  • Publication number: 20100120854

    Abstract: The present invention provides crystalline 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole monohydrate.

    Type: Application

    Filed: June 29, 2006

    Publication date: May 13, 2010

    Applicant: ELI LILLY AND COMPANY

    Inventor: Sreenivasa Reddy Mundla

  • Patent number: 6066740

    Abstract: The present invention provides a process for making 2-amino-2-imidazoline, guanidine, and 2-amino-3,4,5,6-tetrahydroyrimidine derivatives by preparing the corresponding activated 2-thio-subsituted-2-derivative in a two-step, one-pot procedure and by further reacting yields this isolated derivative with the appropriate amine or its salts in the presence of a proton source. The present process allows for the preparation of 2-amino-2-imidazolines, quanidines, and 2-amino-3,4,5,6-tetrahydropyrimidines under reaction conditions that eliminate the need for lengthy, costly, or multiple low yielding steps, and highly toxic reactants. This process allows for improved yields and product purity and provides additional synthetic flexibility.

    Type: Grant

    Filed: November 25, 1997

    Date of Patent: May 23, 2000

    Assignee: The Procter & Gamble Company

    Inventors: Michael Selden Godlewski, Sean Rees Klopfenstein, Sreenivasa Reddy Mundla, William Lee Seibel, Randy Stuart Muth

TGF-β inhibitors

US 7872020 B2

Sreenivasa Reddy Mundla

The present invention provides 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl) -5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole monohydrate, i.e., Formula I.

Figure US07872020-20110118-C00002

EXAMPLE 1 Preparation of 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl-5,6-dihydro-4H -pyrrolo[1,2-b]pyrazole monohydrate

Figure US07872020-20110118-C00008

Galunisertib

1H NMR (CDCl3): δ=9.0 ppm (d, 4.4 Hz, 1H); 8.23-8.19 ppm (m, 2H); 8.315 ppm (dd, 1.9 Hz, 8.9 Hz, 1H); 7.455 ppm (d, 4.4 Hz, 1H); 7.364 ppm (t, 7.7 Hz, 1H); 7.086 ppm (d, 8.0 Hz, 1H); 6.969 ppm (d, 7.7 Hz, 1H); 6.022 ppm (m, 1H); 5.497 ppm (m, 1H); 4.419 ppm (t, 7.3 Hz, 2H); 2.999 ppm (m, 2H); 2.770 ppm (p, 7.2 Hz, 7.4 Hz, 2H); 2.306 ppm (s, 3H); 1.817 ppm (m, 2H). MS ES+: 370.2; Exact: 369.16

ABOVE MOLECULE IS

https://newdrugapprovals.org/2016/05/04/galunisertib/

Galunisertib

Phase III

LY-2157299

CAS No.700874-72-2

 

 

READ MY PRESENTATION ON

Accelerating Generic Approvals, see how you can accelerate your drug development programme

Accelerating Generic Approvals by Dr Anthony Crasto

KEYWORDS   Sreenivasa Mundla Reddy, Managing Director, Sreeni Labs Private Limited, Hyderabad, Telangana, India,  new, economical, scalable routes, early clinical drug development stages, Custom synthesis, custom manufacturing, drug discovery, PHASE 1, PHASE 2, PHASE 3,  API, drugs, medicines

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A Novel Scale Up Model for Prediction of Pharmaceutical Film Coating Process Parameters

 MANUFACTURING  Comments Off on A Novel Scale Up Model for Prediction of Pharmaceutical Film Coating Process Parameters
Jun 072016
 

In the pharmaceutical tablet film coating process, we clarified that a difference in exhaust air relative humidity can be used to detect differences in process parameters values, the relative humidity of exhaust air was different under different atmospheric air humidity conditions even though all setting values of the manufacturing process parameters were the same, and the water content of tablets was correlated with the exhaust air relative humidity. Based on this experimental data, the exhaust air relative humidity index (EHI), which is an empirical equation that includes as functional parameters the pan coater type, heated air flow rate, spray rate of coating suspension, saturated water vapor pressure at heated air temperature, and partial water vapor pressure at atmospheric air pressure, was developed. The predictive values of exhaust relative humidity using EHI were in good correlation with the experimental data (correlation coefficient of 0.966) in all datasets. EHI was verified using the date of seven different drug products of different manufacturing scales. The EHI model will support formulation researchers by enabling them to set film coating process parameters when the batch size or pan coater type changes, and without the time and expense of further extensive testing.

EHI is defined as the following equation:

In general, pharmaceutical film coatings are applied in order to protect core tablets from light or for masking the taste of the active pharmaceutical ingredients. Therefore, the surface state of the coating layer is important to maintain the expected performance. During the coating process, however, the coating layer surface state is affected by the water content of the tablets. In a conventional approach, the water content of drug products is maintained at the validated level by monitoring the product’s temperature and/or the exhaust air temperature during the coating process. In a scale up study, the batch scale and manufacturing equipment are changed according to the progress of the process development stage. At each stage, the water content of drug products is constantly monitored and well-controlled to secure the consistency of the drug product’s quality. In this approach, numerous experiments are necessary to optimize the process parameters in each batch scale. As a result, the costs of materials, human resources, and time for development will become considerable.

A Novel Scale Up Model for Prediction of Pharmaceutical Film Coating Process Parameters

Chemical and Pharmaceutical Bulletin
Vol. 64 (2016) No. 3 p. 215-221

http://doi.org/10.1248/cpb.c15-00644

Conclusion

In this study, the relationship between film coating process parameters and EARH was clarified. In addition, it was confirmed that the EARH affected the water content of tablets. These results indicated that the water content of tablets can be regulated by controlling the EARH. From these results, we proposed the EHI for quantification of the pharmaceutical film coating process. The fitting parameters in the EHI equation were set using the experimental data of 10 drug products and 7 kinds of pan coaters. These fitting parameters of EHI were validated by evaluating the correlation coefficient determined by comparing the calculated values of EARH and the measured experimental values of EARH from various drug products, pan coater scales and coating parameters. The main advantage of the EHI method is that commercial scale coating conditions can be predicted using only one film coating experimental result from a lab-scale pan coater.

/////////pan coater, exhaust air relative humidity index (EHI), scale up, drying ability, atmospheric air, tablet water content

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Preparation and Evaluation of Solid Dispersion Tablets by a Simple and Manufacturable Wet Granulation Method Using Porous Calcium Silicate

 MANUFACTURING  Comments Off on Preparation and Evaluation of Solid Dispersion Tablets by a Simple and Manufacturable Wet Granulation Method Using Porous Calcium Silicate
Jun 072016
 

 

The aim of this study was to prepare and evaluate solid dispersion tablets containing a poorly water-soluble drug using porous calcium silicate (PCS) by a wet granulation method. Nifedipine (NIF) was used as the model poorly water-soluble drug. Solid dispersion tablets were prepared with the wet granulation method using ethanol and water by a high-speed mixer granulator. The binder and disintegrant were selected from 7 and 4 candidates, respectively. The dissolution test was conducted using the JP 16 paddle method. The oral absorption of NIF was studied in fasted rats. Xylitol and crospovidone were selected as the binder and disintegrant, respectively. The dissolution rates of NIF from solid dispersion formulations were markedly enhanced compared with NIF powder and physical mixtures. Powder X-ray diffraction (PXRD) confirmed the reduced crystallinity of NIF in the solid dispersion formulations. Fourier transform infrared (FT-IR) showed the physical interaction between NIF and PCS in the solid dispersion formulations. NIF is present in an amorphous state in granules prepared by the wet granulation method using water. The area under the plasma concentration–time curve (AUC) and peak concentration (Cmax) values of NIF after dosing rats with the solid dispersion granules were significantly greater than those after dosing with NIF powder. The solid dispersion formulations of NIF prepared with PCS using the wet granulation method exhibited accelerated dissolution rates and superior oral bioavailability. This method is very simple, and may be applicable to the development of other poorly water-soluble drugs.

The ‘Biopharmaceutics Classification System’ (BCS) is a very important key word in the research and development of oral formulations. The BCS classifies drugs into four classes depending on the solubility and membrane permeability of the drug. Most oral formulations show drug efficacy by first dissolving in the digestive tract then being absorbed through the membrane of the small intestine, thus entering the circulation. Oral formulations have been developed using various strategies depending on the drug’s BCS class, solubility, and membrane permeability. It was recently estimated that between 40 and 70% of all new chemical entities identified in drug discovery programs are insufficiently soluble in aqueous media………. read all

Conclusion

Solid dispersion formulations of NIF with PCS using the wet granulation method were prepared and evaluated. These formulations exhibited much higher dissolution rates than NIF powder, comparable to ASD. Furthermore, these formulations provided superior bioavailability in rats compared with NIF powder. NIF was present in the amorphous state in the granules after preparation by a wet granulation method using water. The wet granulation method proposed here is very simple, and may be applicable to other poorly water-soluble drugs.

Preparation and Evaluation of Solid Dispersion Tablets by a Simple and Manufacturable Wet Granulation Method Using Porous Calcium Silicate

The ‘Biopharmaceutics Classification System’ (BCS) is a very important key word in the research and development of oral formulations. The BCS classifies drugs into four classes depending on the solubility and membrane permeability of the drug. Most oral formulations show drug efficacy by first dissolving in the digestive tract then being absorbed through the membrane of the small intestine, thus entering the circulation. Oral formulations have been developed using various strategies depending on the drug’s BCS class, solubility, and membrane permeability. It was recently estimated that between 40 and 70% of all new chemical entities identified in drug discovery programs are insufficiently soluble in aqueous media………. read all

Conclusion

Solid dispersion formulations of NIF with PCS using the wet granulation method were prepared and evaluated. These formulations exhibited much higher dissolution rates than NIF powder, comparable to ASD. Furthermore, these formulations provided superior bioavailability in rats compared with NIF powder. NIF was present in the amorphous state in the granules after preparation by a wet granulation method using water. The wet granulation method proposed here is very simple, and may be applicable to other poorly water-soluble drugs.

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Predicting the Occurrence of Sticking during Tablet Production by Shear Testing of a Pharmaceutical Powder

 MANUFACTURING  Comments Off on Predicting the Occurrence of Sticking during Tablet Production by Shear Testing of a Pharmaceutical Powder
Jun 072016
 

A larger SI indicates a greater likelihood that sticking will occur.

Defining SI for Assessing Adhesion of Powder to the Punch

One cause of sticking is that when a powder is being compacted, the adhesive force between powder particles of the tablet and the punch surface exceeds the adhesive forces of powder particles within the tablet. Φp represents the frictional force acting between particles in the powder bed, and Φw represents the frictional force between the powder and the punch surface. The larger these values, the higher the friction and adhesion of the powder. We defined SI, which represents the degree of adhesion of a powder to the punch surface, as the value obtained by dividing Φw by Φp according to the following formula.

Sticking is a failure of pharmaceutical production that occurs when a powder containing a large amount of adhesive is being tableted. This is most frequently observed when long-term tableting is carried out, making it extremely difficult to predict its occurrence during the tablet formula design stage. The efficiency of the pharmaceutical production process could be improved if it were possible to predict whether a particular formulation was likely to stick during tableting. To address this issue, in the present study we prepared tablets composed of blended ibuprofen (Ibu), a highly adhesive drug, and measured the degree of adherence of powder particles to the surface of the tablet punch. We also measured the shear stress of the powder to determine the practical angle of internal friction (Φp) of the powder bed as well as the angle of wall friction (Φw) relative to the punch surface. These values were used to define a sticking index (SI), which showed a high correlation with the amount of Ibu that adhered to the punch during tableting; sticking occurred at SI >0.3. When the amount of lubricant added to the formulation was changed to yield tablets exhibiting different SI values without changing the compounding ratio, sticking did not occur at SI ≤0.3. These results suggest that determining the SI of a pharmaceutical powder before tableting allows prediction of the likelihood of sticking during tableting.

 

Predicting the Occurrence of Sticking during Tablet Production by Shear Testing of a Pharmaceutical Powder

 

///////////sticking, shear stress, internal friction angle, wall friction angle, sticking index, ibuprofen,  Tablet Production, Shear Testing, Pharmaceutical Powder

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An Improved Process for the Preparation of Tenofovir Disoproxil Fumarate

 MANUFACTURING, PROCESS, SYNTHESIS  Comments Off on An Improved Process for the Preparation of Tenofovir Disoproxil Fumarate
Mar 152016
 

 

VIREAD® (tenofovir disoproxil fumarate) Structural Formula Illustration

Tenofovir Disoproxil Fumarate

For full details see end of page

 

PAPER

 

 

Abstract Image

The current three-step manufacturing route for the preparation of tenofovir disoproxil fumarate (1) was assessed and optimized leading to a higher yielding, simpler, and greener process. Key improvements in the process route include the refinement of the second stage through the replacement of the problematic magnesium tert-butoxide (MTB) with a 1:1 ratio of a Grignard reagent and tert-butanol. The development of a virtually solvent-free approach and the establishment of a workup and purification protocol which allows the isolation of a pure diethyl phosphonate ester (8) was achieved

 

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see………….http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00364

An Improved Process for the Preparation of Tenofovir Disoproxil Fumarate

Department of Chemistry, Natural and Agricultural Sciences, University of Pretoria, 2 Lynnwood Road, Hatfield, 0002, Gauteng, South Africa
Department of Engineering and Technology Management, University of Pretoria, Pretoria, South Africa
§ Pharmaceutical Manufacturing Technology Centre, University of Limerick, Limerick, V94 T9PX, Republic of Ireland
iThemba Pharmaceuticals, Modderfontein, 1645, Gauteng South Africa
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.5b00364
Publication Date (Web): March 04, 2016
Copyright © 2016 American Chemical Society

University of Pretoria

Department of Chemistry, Natural and Agricultural Sciences, University of Pretoria, 2 Lynnwood Road, Hatfield, 0002, Gauteng, South Africa

Map of Department of Chemistry, Natural and Agricultural Sciences, University of Pretoria, 2 Lynnwood Road, Hatfield, 0002, Gauteng, South Africa

///////

Tenofovir Disoproxil Fumarate

5-[[(1R)-2-(6-Amino-9H-purin-9-yl)-1-methylethoxy]methyl]-2,4,6,8-tetraoxa-5-phosphanonanedioic Acid 1,9-Bis(1-methylethyl) Ester 5-Oxide (2E)-2-Butenedioate; GS 4331-05; PMPA Prodrug; Tenofovir DF; Virea; Viread;

GILEAD-4331-300

201341-05-1 – free base, (Tenofovir Disoproxil

 fumarate 202138-50-9
113-115°C (dec.)
CAS No.: 202138-50-9
Name: Tenofovir disoproxil fumarate
Molecular Structure:
Molecular Structure of 202138-50-9 (Tenofovir disoproxil fumarate)
Formula: C19H30N5O10P.C4H4O4
Molecular Weight: 635.51
Synonyms: TDF;PMPA prodrug;Tenofovir Disoproxil Fumarate [USAN];9-((R)-2-((Bis(((isopropoxycarbonyl)oxy)methoxy)phosphinyl)methoxy)propyl)adenine, fumarate;201341-05-1;Bis(NeopentylOC)PMPA;Viread;GS 4331-05 (*1:1 Fumarate salt*);Viread (*1:1 Fumarate salt*);Truvada;Tenofovir DF;[[(2R)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-(propan-2-yloxycarbonyloxymethoxy)phosphoryl]oxymethyl propan-2-yl carbonate;
Usage
tyrosinase inhibitor used for skin lightening and anti-melasma
Usage
An acyclic phosphonate nucleotide analog and selective HIV-1 RT inhibitor
Usage
Acyclic phosphonate nucleotide analogue; reverse transcriptase inhibitor. Used as an anti-HIV agent. Antiviral.

 

Tenofovir disoproxil is an antiretroviral medication used to prevent and treat HIV/AIDS and to treat chronic hepatitis B.[1] The active substance is tenofovir, while tenofovir disoproxil is a prodrug that is used because of its better absorption in the gut.

The drug is on the World Health Organization’s List of Essential Medicines, the most important medications needed in a basic health system.[2] It is marketed by Gilead Sciences under the trade name Viread (as the fumarate, TDF).[3] As of 2015 the cost for a typical month of medication in the United States is more than 200 USD.[4]

http://www.intmedpress.com/journals/avt/iframePopup_fig.cfm?img=c32b4107-6d95-47c7-bb57-45390ba123b1

Medical uses

  • HIV-1 infection: Tenofovir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 2 years of age and older.[5] This indication is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts in controlled studies of tenofovir in treatment-naive and treatment-experienced adults.
  • Tenofovir is indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older.[5][6]

HIV risk reduction

A Cochrane review examined the use of tenofovir for prevention of HIV before exposure. It found that both tenofovir alone and the tenofovir/emtricitabine combination decreased the risk of contracting HIV.[7]

The U. S. Centers for Disease Control and Prevention (CDC) conducted a study in partnership with the Thailand Ministry of Public Health to ascertain the effectiveness of providing people who inject drugs illicitly with daily doses of the antiretroviral drug tenofovir as a prevention measure. The results of the study were released in mid-June 2013 and revealed a 48.9%-reduced incidence of the virus among the group of subjects who received the drug, in comparison to the control group who received a placebo. The principal investigator of the study stated: “We now know that pre-exposure prophylaxis can be a potentially vital option for HIV prevention in people at very high risk for infection, whether through sexual transmission or injecting drug use.”[8]

Adverse effects

The most common side effects associated with tenofovir include nausea, vomiting, diarrhea, and asthenia. Less frequent side effects include hepatotoxicity, abdominal pain, and flatulence.[9] Tenofovir has also been implicated in causing renal toxicity, particularly at elevated concentrations.[10]

Tenofovir can cause acute renal failure, Fanconi syndrome, proteinuria, or tubular necrosis.[citation needed] These side effects are due to accumulation of the drug in proximal tubules.[citation needed] Tenofovir can interact with didanosine by increasing didanosine’s concentration.[citation needed] It also decreases the concentration of atazanavir sulfate.[citation needed]

Mechanism of action

Tenofovir is a defective adenosine nucleotide that selectively interferes with the action of reverse transcriptase, but only weakly interferes with mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.[11] Tenofovir prevents the formation of the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation. A phosphodiester bond cannot be formed because the tenofovir molecule lacks an —OH group on the 3′ carbon of its deoxyribose sugar.[11] Once incorporated into a growing DNA strand, tenofovir causes premature termination of DNA transcription. The drug is classified as a nucleotide analogue reverse transcriptase inhibitor (NRTI), that inhibits reverse transcriptase.[11] Reverse transcriptase is a crucial viral enzyme in retroviruses such as human immunodeficiency virus (HIV) and in hepatitis B virus infections.[5]

History

Tenofovir was initially synthesized by Antonín Holý at the Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic in Prague. The patent[12] filed by Holý in 1984 makes no mention of the potential use of the compound for the treatment of HIV infection, which had only been discovered one year earlier.

In 1985, De Clercq and Holý described the activity of PMPA against HIV in cell culture.[13] Shortly thereafter, a collaboration with the biotechnology company Gilead Sciences led to the investigation of PMPA’s potential as a treatment for HIV infected patients. In 1997 researchers from Gilead and the University of California, San Francisco demonstrated that tenofovir exhibits anti-HIV effects in humans when dosed by subcutaneous injection.[14]

The initial form of tenofovir used in these studies had limited potential for widespread use because it was not absorbed when administered orally. A medicinal chemistry team at Gilead developed a modified version of tenofovir, tenofovir disoproxil.[15] This version of tenofovir is often referred to simply as “tenofovir”. In this version of the drug, the two negative charges of the tenofovir phosphonic acid group are masked, thus enhancing oral absorption.

Tenofovir disoproxil was approved by the U.S. FDA on October 26, 2001, for the treatment of HIV, and on August 11, 2008, for the treatment of chronic hepatitis B.[16][17]

Drug forms

Tenofovir disoproxil is a prodrug form of tenofovir. It is also marketed under the brand name Reviro by Dr. Reddy’s Laboratories. Tenofovir is also available in a fixed-dose combination with emtricitabine in a product with the brand name Truvada for once-a-day dosing. Efavirenz/emtricitabine/tenofovir disoproxil (brand name Atripla) — a fixed-dose triple combination of tenofovir, emtricitabine, and efavirenz, was approved by the FDA on 12 July 2006 and is now available, providing a single daily dose for the treatment of HIV.

Therapeutic drug monitoring

Tenofovir may be measured in plasma by liquid chromatography. Such testing is useful for monitoring therapy and to prevent drug accumulation and toxicity in people with kidney or liver problems.[18][19][20]

PATENT

http://www.google.com/patents/EP2545063A2?cl=en

Tenofovir Disoproxil is chemically known as 9-[-2-(R)-[[bis [[(isopropoxycarbonyl) oxy]methoxy] phosphinoyl]methoxy]propyl]-adenine, having the following structural formula-I.

Formula-I

Tenofovir is a highly potent antiviral agent, particularly for the therapy or prophylaxis of retroviral infections and belongs to a class of drugs called Nucleotide Reverse Transcriptase Inhibitors (NRTI) which blocks reverse transcriptase an enzyme crucial to viral production in HIV-infected people.

Tenofovir Disoproxil and its pharmaceutically acceptable salts were first disclosed in US 5,922,695. This patent discloses the preparation of Tenofovir Disoproxil by the esterification of Tenofovir with chloromethyl isopropyl carbonate using l-methyl-2- pyrrolidinone and triethylamine. In this patent Tenofovir Disoproxil is converted into its Fumarate salt without isolation. PCT Publication WO 2008007392 discloses process for the preparation of Tenofovir Disoproxil fumarate, wherein the isolated crystalline Tenofovir Disoproxil is converted into fumarate salt.

Tenofovir Disoproxil processes in the prior art are similar to process disclosed in product patent US 5,922,695. According to the prior art processes, Tenofovir Disoproxil fumarate obtained is having low yields and also show the presence of impurities such as dimers.

scheme- 1.

Tenofovir disoproxil chloromethyl isopropyl carbonate

Tenofovir disoproxil fumarate

Example 1 : Process for the preparation of Tenofovir Disoproxil fumarate

Toluene (500 ml) was added to the Tenofovir (100 gm) and stirred at room temperature. To this triethylamine (66.31 gm) was added, temperature was raised to 90° C and water was collected by azeotropic distillation at 110°C. Toluene was completely distilled under vacuum at same temperature. The reaction mixture was cooled to room temperature and to this a mixture of N-methyl pyrrolidine (300 gm), triethylamine (66.31 gm), Tetrabutyl ammonium bromide (52.8 gm) and trimethyl silyl chloride (17.8 gm) were added. The above reaction mixture was heated to 50-55 °C and was added slowly chloromethyl. isopropyl carbonate (CMIC) and maintained the reaction mixture at 50-55°C for 5 hrs. (Qualitative HPLC analysis shows about 85% product formation). The above reaction mixture was cooled to room temperature and filtered. The filtrate was added to DM water at 5-10°C and extract with dichloromethane. The combined dichloromethane layer was concentrated under vacuum and the crude was Co-distilled with cyclohexane and this crude was taken into isopropyl alcohol (1000 ml). To this fumaric acid (38 gm) was added and temperature was raised to 50° C. The reaction mixture was filtered and filtrate was cooled to 5-10° C. The obtained solid was filtered and washed with isopropyl alcohol. The compound was dried under vacuum to yield Tenofovir Disoproxil fumarate (140 gm).

Example-2 : Preparation of Tenofovir

N-methyl-2-pyrrolidone (25 gm) was taken along with toluene (150 gm) into a reaction vessel. l-(6-amino-purin-9-yl)-propan-2-ol (100 gm); toluene-4-sulfonic acid diethoxy phosphoryl methyl ester (200 gm) and magnesium ter-butoxide (71.2 gm) were also taken at’ 25-35°C. Temperature was raised to 74-75 °C and maintained for 5-6hrs. After completion of reaction, acetic acid (60 gm) was added and maintained for 1 hr. Later aq.HBr (332 gm) was taken and heated to 90-95 °C. After reaction completion, salts were filtered and filtrate was subjected to washings with water and extracted into methylene dichloride. Later pH was adjusted using CS lye below 10 °C. Tenofovir product was isolated using acetone.

Yield: 110 gm.

Example 3 : Preparation of Tenofovir disoproxil

(R)-9-[2-(phosphonomethoxy)propyl]adenine (25 gm), triethyl amine (25 ml) and cyclohexane (200 ml) were combined and heated to remove water and the solvent was distilled off under vacuum. The reaction mass was cooled to room temperature N-methyl pyrrolidinone (55 ml), triethyl amine (25 ml) and tetra butyl ammonium bromide(54 gms) were added to the reaction mixture. The reaction mass was heated to 50-60°C and chloromethyl isopropyl carbonate (65 gm) was added and maintained for 4-8 hrs at 50- 60°C and then cooled to 0°C. The reaction mass was diluted with chilled water or ice and precipitated solid product was filtered. The mother liquor was extracted with methylene chloride (150 ml). The methylene chloride layer was washed with water (200 ml). The filtered solid and the methylene chloride layer were combined and washed with water and the solvent was distilled under vacuum. Ethyl acetate was charged to the precipitated solid. The reaction mass was then cooled to 0-5 °C and maintained for 6 hrs. The solid was filtered and dried to produce Tenofovir disoproxil (45 gm).

CLIPS

The reaction of chloromethyl chloroformate (I) with isopropyl alcohol (II) by means of pyridine or triethylamine in ether gives the mixed carbonate (III), which is then condensed with (R)-PMPA (IV) by means of diisopropyl ethyl-amine in DMF.

US 5922695; WO 9804569

CLIP 2

1) The protection of isobutyl D-(+)-lactate (I) with dihydropyran (DHP)/HCl in DMF gives the tetrahydropyranyloxy derivative (II), which is reduced with bis(2-methoxyethoxy)aluminum hydride in refluxing ether/ toluene yielding 2(R)-(tetrahydropyranyloxy)-1-propanol (III). The tosylation of (III) with tosyl chloride as usual affords the expected tosylate (VI), which is condensed with adenine (V) by means of Cs2CO3 in hot DMF, affording 9-[2(R)-(tetrahydropyranyloxy)propyl]adenine (VI). The deprotection of (VI) with sulfuric acid affords 9-[2(R)-hydroxypropyl]adenine (VII), which is N-benzoylated with benzoyl chloride/chlorotrimethylsilane in pyridine to give the benzamide (VIII), which is condensed with tosyl-oxymethylphosphonic acid diisopropyl ester (IX) by means of NaH in DMF to yield 9-[2(R)-(diisopropoxyphosphorylmethoxy)propyl]adenine (X). Finally, this compound is hydrolyzed by means of bromotrimethylsilane in acetonotrile.

 

 

2) The reaction of the previously described (R)-2-(2-tetrahydropyranyloxy)-1-propanol (III) with benzyl bromide (XI) by means of NaH in DMF, followed by a treatment with Dowex 50X, gives 1-benzyloxy-2(R)-propanol (XII), which is condensed with tosyloxymethylphosphonic acid diisopropyl ester (IX) by means of NaH in THF, yielding 2-benzyloxy-1(R)-methylethoxymethylphosphonic acid diisopropyl ester (XIII). The hydrogenolysis of (XIII) over Pd/C in methanol affords 2-hydroxy-1(R)-methylethoxymethylphosphonic acid diisopropyl ester (XIV), which is tosylated with tosyl chloride/dimethyl-aminopyridine in pyridine to give the expected tosylate (XV). The condensation of (XV) with adenine (VI) by means of Cs2CO3 in hot DMF yields 9-[2(R)-(diisopropoxyphosphorylmethoxy)propyl]adenine (X), which is finally hydrolyzed as before.

 

3) The catalytic hydrogenation of (S)-glycidol (XVI) over Pd/C gives the (R)-1,2-propanediol (XVII), which is esterified with diethyl carbonate (XVIII)/NaOEt, yielding the cyclic carbonate (XIX). The reaction of (XIX) with adenine (V) by means of NaOH in DMF affords 9-[2(R)-hydroxypropyl]adenine (VII), which is condensed with tosyloxymethylphosphonic acid diethyl ester (XX) by means of lithium tert-butoxide in THF, giving 9-[2(R)-(diethoxyphosphorylmethoxy)propyl]adenine (XXI). Finally, this compound is hydrolyzed with bromotrimethylsilane as before. Compound (XX) is obtained by reaction of diethyl phosphite (XXII) with paraformaldehyde, yielding hydroxy- methylphosphonic acid diethyl ester (XXIII), which is finally tosylated as usual.

 

References

  1. R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, California, 2008, pp. 1490–1492.

External links

WO2008007392A2 Jul 11, 2007 Jan 17, 2008 Matrix Lab Ltd Process for the preparation of tenofovir
US5922695 Jul 25, 1997 Jul 13, 1999 Gilead Sciences, Inc. Antiviral phosphonomethyoxy nucleotide analogs having increased oral bioavarilability
WO2015051874A1 Sep 22, 2014 Apr 16, 2015 Zentiva, K.S. An improved process for the preparation of tenofovir disoproxil and pharmaceutically acceptable salts thereof
CN103360425A * Apr 1, 2012 Oct 23, 2013 安徽贝克联合制药有限公司 Synthesis method of tenofovir disoproxil and fumarate thereof
CN103374038A * Apr 11, 2012 Oct 30, 2013 广州白云山制药股份有限公司广州白云山制药总厂 Preparation method of antiviral medicine
CN103848868A * Dec 4, 2012 Jun 11, 2014 蚌埠丰原涂山制药有限公司 Method for preparing tenofovir
CN103848869A * Dec 4, 2012 Jun 11, 2014 上海医药工业研究院 Method for preparing tenofovir
CN103980319A * Apr 24, 2014 Aug 13, 2014 浙江外国语学院 Preparation method of tenofovir
CN103980319B * Apr 24, 2014 Dec 2, 2015 浙江外国语学院 一种泰诺福韦的制备方法
EP2860185A1 Oct 9, 2013 Apr 15, 2015 Zentiva, k.s. An improved process for the preparation of Tenofovir disoproxil and pharmaceutically acceptable salts thereof

 

 

The chemical name of tenofovir disoproxil fumarate is 9-[(R)-2[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C19H30N5O10P • C4H4O4 and a molecular weight of 635.52. It has the following structural formula:

 

VIREAD® (tenofovir disoproxil fumarate) Structural Formula Illustration

Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in distilled water at 25 °C. It has an octanol/phosphate buffer (pH 6.5) partition coefficient (log p) of 1.25 at 25 °C.

VIREAD is available as tablets or as an oral powder.

VIREAD tablets are for oral administration in strengths of 150, 200, 250, and 300 mg of tenofovir disoproxil fumarate, which are equivalent to 123, 163, 204 and 245 mg of tenofovir disoproxil, respectively. Each tablet contains the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The 300 mg tablets are coated with Opadry II Y-3010671-A, which contains FD&C blue #2 aluminum lake, hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin. The 150, 200, and 250 mg tablets are coated with Opadry II 32K-18425, which contains hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin.

VIREAD oral powder is available for oral administration as white, taste-masked, coated granules containing 40 mg of tenofovir disoproxil fumarate per gram of oral powder, which is equivalent to 33 mg of tenofovir disoproxil. The oral powder contains the following inactive ingredients: mannitol, hydroxypropyl cellulose, ethylcellulose, and silicon dioxide.

enofovir disoproxil
Tenofovir disoproxil structure.svg
Systematic (IUPAC) name
Bis{[(isopropoxycarbonyl)oxy]methyl} ({[(2R)-1-(6-amino-9H-purin-9-yl)-2-propanyl]oxy}methyl)phosphonate
Clinical data
Trade names Viread
AHFS/Drugs.com monograph
Pregnancy
category
  • AU: B3
  • US: B (No risk in non-human studies)
Routes of
administration
Oral (tablets)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 25%
Identifiers
CAS Number 201341-05-1
ATC code J05AF07 (WHO)
PubChem CID 5481350
ChemSpider 4587262
UNII F4YU4LON7I
ChEBI CHEBI:63717
NIAID ChemDB 080741
Chemical data
Formula C19H30N5O10P
Molar mass 519.443 g/mol
Tenofovir
Tenofovir structure.svg
Systematic (IUPAC) name
({[(2R)-1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy}methyl)phosphonic acid
Clinical data
MedlinePlus a602018
Routes of
administration
In form of prodrugs
Pharmacokinetic data
Protein binding < 1%
Biological half-life 17 hours
Excretion Renal
Identifiers
CAS Number 147127-20-6 Yes
ATC code None
PubChem CID 464205
DrugBank DB00300 Yes
ChemSpider 408154 Yes
UNII 99YXE507IL Yes
KEGG D06074 Yes
ChEBI CHEBI:63625
ChEMBL CHEMBL483 Yes
Synonyms 9-(2-Phosphonyl-methoxypropyly)adenine (PMPA)
Chemical data
Formula C9H14N5O4P
Molar mass 287.213 g/mol

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Heterogeneous catalysis and catalyst recycling

Heterogeneous catalysis is a type of catalysis in which the catalyst occupies a different phase from the reactants and products. This may refer to the physical phase — solid, liquid or gas — but also to immiscible fluids. Heterogeneous catalysts can be more easily recycled than homogeneous, but characterization of the catalyst and optimization of properties can be more difficult.

Heterogeneous catalysis is widely used in the synthesis of bulk and fine chemicals. In a general, small scale batch reaction, the catalyst, reactants, and solvent are stirred together until completion of the reaction, after which the bulk liquid is separated by filtration. The catalyst can then be collected for either recycling or disposal. In a continuous process, the catalyst can be fixed in space and the reaction mixture allowed to flow over it. The reaction and separation are thus combined in a single step, and the catalyst remains in the reactor for easy recycling. Beyond facilitating separation, thecatalyst may have improved lifetime due to decreased exposure to the environment, and reaction rates and turnover numbers can be enhanced through the use of high concentrations of a catalyst with continuous recycling. The benefits of flow are seemingly obvious, yet it has only recently become a widely adopted method for bench-scale synthesis.1

Hydrogenation of ethene on a solid surface

The most common application of continuous heterogeneous catalysis is in hydrogenation reactions,2 where the handling and separation of solid precious metal catalysts is not only tedious but hazardous under batch conditions. Moreover, the mixing between the three phases in a hydrogenation is generally quite poor. The use of a flow reactor gives a higher interfacial area between phases and thus more efficient reactions. For example, Ley and co-workers found that the hydrogenation of alkene 1 to 2 was challenging in batch, requiring multiple days at 80 bar of H2 (Scheme 1).3 Using a commercially available H-Cube® reactor, the reaction time was shortened to 4 hours, the pressure reduced to 60 bar, and manual separation and recycling of the catalyst from the reaction was unnecessary. The increased efficiency is due to a combination of improved mixing of the three phases, as well as the continuous recycling and high local concentration of the catalyst. The H-Cube offers a further safety advantage because it generates hydrogen gas on demand from water, obviating the need for a high pressure H2 tank.

Hydrogenation with an immobilized heterogeneous catalyst.
Scheme 1 Hydrogenation with an immobilized heterogeneous catalyst.

Homogeneous catalysis has many advantages over heterogeneous catalysis, such as increased activity and selectivity, and mechanisms of action that are more easily understood. Unfortunately, the difficulty associated with separating homogeneous catalysts from the product is a significant hindrance to their large scale application. In an attempt to combine the high activity of homogeneous catalysis with the practical advantageous of heterogeneous catalysis, there has been much research into immobilizing homogeneous catalysts on solid supports.4 This is generally achieved by linking thecatalyst to the surface of an insoluble solid such as silica or polymer beads. As was the case in batch hydrogenation reactions, the process of separating and purifying the catalyst is inefficient, potentially dangerous, and may lead to degradation and loss of material. Performing these reactions in a flow system can help overcome these problems.5 A highly efficient example has been demonstrated by van Leeuwen and co-workers, who sought to immobilize a catalyst used in transfer hydrogenation reactions (Scheme 2).6Their test reaction was the asymmetric reduction of acetophenone; homogeneousreduction with ruthenium and ligand 3 provided 88% conversion and 95% enantioselectivity. The ligand was then covalently linked to silica gel through the benzyl group to form 4. Using this heterogenized system under batch conditions, conversion dropped to 38% on the same time scale, and a slight decrease in enantioselectivity occurred. A reduction in activity of a catalyst upon immobilization is common, so highly efficient recycling is required. Unfortunately, when attempting to re-use the catalyst after filtration, significant degradation and leaching occurred. The catalyst was then packed in a glass column for application in flow chemistry. After a short optimization of flow rate, 95% conversion and 90% ee were obtained. Importantly, the reaction could be run continuously for up to one week without significant degradation in conversion or enantioselectivity. The physical isolation of catalyst species on the solid support is suggested to contribute to the long catalystlifetime. Interestingly, the basic potassium tert-butoxide additive was only required initially to activate the catalyst, and the reaction could subsequently be run without additional base, allowing the product to be isolated completely free of additives. It is important to note, on top of the decreased activity due to modification, that leaching from cleavage off the solid support and the increased cost of the catalyst due to derivatization are all potential downsides of immobilization of catalysts. In some instances, a seemingly heterogeneous catalyst has been shown to leach active homogeneous species into solution.7 However, as can be seen above, robust systems can be developed which do combine the best features of both homogeneous and heterogeneous catalysis.

Immobilization of a homogeneous catalyst on a solid support.
Scheme 7 Immobilization of a homogeneous catalyst on a solid support.

Another important method for recycling expensive catalysts is through the use of liquid–liquid biphasic conditions where the catalyst and reactants can be separated by extraction upon completion of the reaction. Such processes have already been utilized on the medium and large scale in a continuous or semi-continuous fashion.8,9 Recycling on a small scale is typically done through batch liquid–liquid extractions, but examples using continuous methods are increasing.10-13 A recent automated small scale recycling of a biphasic catalyst system was demonstrated by the George group in the continuous oxidation of citronellol (Scheme 3).14A highly fluorinated porphyrin was used as the photocatalyst, and a combination of hydrofluoroether (HFE) and scCO2 was used as the solvent. Under high pressure flow conditions, a single phase was observed. Depressurization occurred after the reactor, resulting in two phases – the organic product in one, and the catalyst and HFE in the other. The denser, catalyst-containing fluorous phase was continuously pumped back through the reactor. With this method, the catalyst was recycled 10 times while maintaining 75% of its catalytic activity, giving an increase in TON of approximately 27-fold compared to previous batch conditions. Some leaching of the fluorinated catalyst into the organic product was observed, accounting for the decreased activity over time.

Automated recycling of a biphasic catalyst system.
Scheme 3 Automated recycling of a biphasic catalyst system.

Examples of heterogeneous catalysisThe hydrogenation of a carbon-carbon double bondThe simplest example of this is the reaction between ethene and hydrogen in the presence of a nickel catalyst.In practice, this is a pointless reaction, because you are converting the extremely useful ethene into the relatively useless ethane. However, the same reaction will happen with any compound containing a carbon-carbon double bond.One important industrial use is in the hydrogenation of vegetable oils to make margarine, which also involves reacting a carbon-carbon double bond in the vegetable oil with hydrogen in the presence of a nickel catalyst.Ethene molecules are adsorbed on the surface of the nickel. The double bond between the carbon atoms breaks and the electrons are used to bond it to the nickel surface.

Hydrogen molecules are also adsorbed on to the surface of the nickel. When this happens, the hydrogen molecules are broken into atoms. These can move around on the surface of the nickel.

If a hydrogen atom diffuses close to one of the bonded carbons, the bond between the carbon and the nickel is replaced by one between the carbon and hydrogen.

That end of the original ethene now breaks free of the surface, and eventually the same thing will happen at the other end.

As before, one of the hydrogen atoms forms a bond with the carbon, and that end also breaks free. There is now space on the surface of the nickel for new reactant molecules to go through the whole process again.


Catalytic converters

Catalytic converters change poisonous molecules like carbon monoxide and various nitrogen oxides in car exhausts into more harmless molecules like carbon dioxide and nitrogen. They use expensive metals like platinum, palladium and rhodium as the heterogeneous catalyst.

The metals are deposited as thin layers onto a ceramic honeycomb. This maximises the surface area and keeps the amount of metal used to a minimum.

Taking the reaction between carbon monoxide and nitrogen monoxide as typical:

Catalytic converters can be affected by catalyst poisoning. This happens when something which isn’t a part of the reaction gets very strongly adsorbed onto the surface of the catalyst, preventing the normal reactants from reaching it.Lead is a familiar catalyst poison for catalytic converters. It coats the honeycomb of expensive metals and stops it working.In the past, lead compounds were added to petrol (gasoline) to make it burn more smoothly in the engine. But you can’t use a catalytic converter if you are using leaded fuel. So catalytic converters have not only helped remove poisonous gases like carbon monoxide and nitrogen oxides, but have also forced the removal of poisonous lead compounds from petrol.


The use of vanadium(V) oxide in the Contact Process

During the Contact Process for manufacturing sulphuric acid, sulphur dioxide has to be converted into sulphur trioxide. This is done by passing sulphur dioxide and oxygen over a solid vanadium(V) oxide catalyst.

This example is slightly different from the previous ones because the gases actually react with the surface of the catalyst, temporarily changing it. It is a good example of the ability of transition metals and their compounds to act as catalysts because of their ability to change their oxidation state.
The sulphur dioxide is oxidised to sulphur trioxide by the vanadium(V) oxide. In the process, the vanadium(V) oxide is reduced to vanadium(IV) oxide.The vanadium(IV) oxide is then re-oxidised by the oxygen.This is a good example of the way that a catalyst can be changed during the course of a reaction. At the end of the reaction, though, it will be chemically the same as it started.

 

c1

 

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  2. M. Irfan, T. N. Glasnov and C. O. Kappe, ChemSusChem, 2011, 4, 300–316 
  3. C. F. Carter, I. R. Baxendale, M. O’Brien, J. P. V. Pavey and S. V. Ley, Org. Biomol. Chem., 2009, 7, 4594–4597 .
  4. P. McMorn and G. J. Hutchings, Chem. Soc. Rev., 2004, 33, 108–122.
  5. S. Ceylan and A. Kirschning, in Recoverable and Recyclable Catalysts, ed. M. Benaglia, John Wiley & Sons Ltd, 2009, pp. 379–410 .
  6. A. J. Sandee, D. G. I. Petra, J. N. H. Reek, P. C. J. Kamer and P. W. N. M. Van Leeuwen, Chem.–Eur. J., 2001, 7, 1202–1208 
  7. M. Pagliaro, V. Pandarus, R. Ciriminna, F. Belénd and P. D. Cerà, ChemCatChem, 2012, 4, 432–445 .
  8. C. W. Kohlpaintner, R. W. Fischer and B. Cornils, Appl. Catal., A, 2001, 221, 219–225 
  9. W. A. Herrmann, C. W. Kohlpaintner, H. Bahrmann and W. Konkol, J. Mol. Catal., 1992, 73, 191 
  10. A. B. Theberge, G. Whyte, M. Frenzel, L. M. Fidalgo, R. C. R. Wootton and W. T. S. Huck, Chem. Commun., 2009, 6225–6227 .
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  12. E. Perperi, Y. Huang, P. Angeli, G. Manos, C. R. Mathison, D. J. Cole-Hamilton, D. J. Adams and E. G. Hope, Dalton Trans., 2004, 2062–2064 .
  13. S. Liu, T. Fukuyama, M. Sato and I. Ryu, Org. Process Res. Dev., 2004, 8, 477–481 
  14. T. Fukuyama, M. T. Rahman, M. Sato and I. Ryu, Synlett, 2008, 151–163 
  15. J. F. B. Hall, X. Han, M. Poliakoff, R. A. Bourne and M. W. George, Chem. Commun., 2012, 48, 3073–3075 .
  16. R. A. Bourne, X. Han, M. Poliakoff and M. W. George, Angew. Chem., Int. Ed., 2009, 48, 5322 

 

 

 

 

 

 

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Flow chemistry can make processes greener….Swern oxidation

 MANUFACTURING, PROCESS, SYNTHESIS  Comments Off on Flow chemistry can make processes greener….Swern oxidation
Jul 202015
 

The Swern oxidation, named after Daniel Swern, is a chemical reaction whereby a primary or secondary alcohol is oxidized to an aldehyde or ketone using oxalyl chloride,dimethyl sulfoxide (DMSO) and an organic base, such as triethylamine.The reaction is known for its mild character and wide tolerance of functional groups.

The Swern oxidation.

The by-products are dimethyl sulfide (Me2S), carbon monoxide (CO), carbon dioxide (CO2) and — when triethylamine is used as base — triethylammonium chloride (Et3NHCl). Two of the by-products, dimethyl sulfide and carbon monoxide, are very toxic volatile compounds, so the reaction and the work-up needs to be performed in a fume hood.Dimethyl sulfide is a volatile liquid (B.P. 37 °C) with an extremely unpleasant odour.

The first step of the Swern oxidation is the low-temperature reaction of dimethyl sulfoxide (DMSO), 1a, formally as resonance contributor 1b, with oxalyl chloride, 2. The first intermediate, 3, quickly decomposes giving off CO2 and CO and producing chloro(dimethyl)sulfonium chloride, 4.

Dimethylchlorosulfonium chloride formation.

After addition of the alcohol 5, the chloro(dimethyl)sulfonium chloride 4 reacts with the alcohol to give the key alkoxysulfonium ion intermediate, 6. The addition of at least 2 equivalents of base — typically triethylamine — will deprotonate the alkoxysulfonium ion to give the sulfur ylide 7. In a five-membered ring transition state, the sulfur ylide 7decomposes to give dimethyl sulfide and the desired ketone (or aldehyde) 8.

 

 

Dimethyl sulfide, a byproduct of the Swern oxidation, is one of the most foul odors known in organic chemistry. Human olfactory glands can detect this compound in concentrations as low as 0.02 to 0.1 parts per million. A simple remedy for this problem is to rinse used glassware with bleach (usually containing sodium hypochlorite), which will oxidize the dimethyl sulfide, eliminating the smell.

The reaction conditions allow oxidation of acid-sensitive compounds, which might decompose under the acidic conditions of a traditional method such as Jones oxidation. For example, in Thompson & Heathcock’s synthesis of the sesquiterpene isovelleral,the final step uses the Swern protocol, avoiding rearrangement of the acid-sensitive cyclopropanemethanol moiety.

IsovelleralPreparationViaSwernOxidation.png

Rapid, exothermic reactions are challenging to do in batch reactors. Reagents such as organometallics, strong bases, and highly active electrophiles are often added slowly to a reaction mixture under energy-intensive cryogenic conditions to prevent an uncontrollable exotherm. Quenching of these high-energy reagents may again require low temperature. This issue is scale dependent,1 and without proper precautions, both the likelihood and hazard of a runaway reaction increase with the size of a reactor.

The high surface area to volume ratio found in flow reactors makes heat transfer more efficient than in batch, allowing rapid removal of thermal energy given off. These features serve to give the chemist or engineer more control over reaction temperature and reduces the risk of thermal runaway.

Many instances have been reported of reactions being performed safely at 0 °C or room temperature in flow that would require cryogenic conditions in batch.2,3,4 This has a further benefit on the overall processing time, as the reaction will occur faster at the elevated temperature and inefficient cooling and warming steps are avoided. A remarkable example demonstrating these principles is the room temperature Swern oxidation reaction by Yoshida and co-workers .5

The Swern reaction is a reliable procedure for converting alcohols to ketones and aldehydes using DMSOactivated by an electrophile (typically COCl2 or TFAA) as the oxidant. In batch, the reaction takes place over three exothermic steps, each of which requires dropwise addition of reagents at cryogenic temperatures.6, 7

PROCESS TO FLOW

When converting the process to flow, the Yoshida group found that the Swern oxidation could be done at room temperature with good yields and purity. Moreover, instead of having reaction times on the order of minutes or hours, the whole process was completed in seconds. They attributed the success of their process to the precise temperature control that can be obtained in flow systems, as well as the ability to quickly transfer unstable intermediates to subsequent steps. Using only a series of syringe pumps, stainless steel tubing, and commercial micromixers, they could prepare over 10 grams of material per hour. Being able to perform reactions on species with very short lifetimes is another general advantage of performing reactions in flow.8

 

Room temperature Swern oxidation.
Scheme  Room temperature Swern oxidation.

 

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MORE……..

http://thalesnano.com/products/IceCube

 

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The Swern oxidation. The center column (green background) shows the desired chemical path, with added reagents shown in black boxes. The outer columns (red background) show the potential chemical pathways for side-product formation (8 and 9).

http://www.mdpi.com/2227-9717/2/1/24/htm

REF

  1. R. L. Hartman, J. P. McMullen and K. F. Jensen, Angew. Chem., Int. Ed., 2011, 50, 7502–7519 
  2. V. Hessel, C. Hofmann, H. Löwe, A. Meudt, S. Scherer, F. Schönfeld and B. Werner, Org. Process Res. Dev., 2004, 8, 511–523 Search PubMed.
  3. A. Nagaki, Y. Tomida, H. Usutani, H. Kim, N. Takabayashi, T. Nokami, H. Okamoto and J.-i. Yoshida, Chem.–Asian J., 2007, 2, 1513–1523 
  4. T. Gustafsson, H. Sörensen and F. Pontén, Org. Process Res. Dev., 2012, 16, 925–929 Search PubMed.
  5. T. Kawaguchi, H. Miyata, K. Ataka, K. Mae and J.-I. Yoshida, Angew. Chem., Int. Ed., 2005, 44, 2413–2416
  6. A. K. Sharma and D. Swern, Tetrahedron Lett., 1974, 15, 1503–1506 Search PubMed.
  7. A. K. Sharma, T. Ku, A. D. Dawson and D. Swern, J. Org. Chem., 1975, 40, 2758–2764 
  8. J.-i. Yoshida, Chem. Rec., 2010, 10, 332–341 

 

 

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

 MANUFACTURING, SYNTHESIS, Uncategorized  Comments Off on A Green and Sustainable Approach: Celebrating the 30th Anniversary of the Asymmetric l-Menthol Process
Feb 052015
 

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

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

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

  1. Makoto Emura* and
  2. Hiroyuki Matsuda

Article first published online: 18 NOV 2014

DOI: 10.1002/cbdv.201400063

Issue

Chemistry & Biodiversity

Chemistry & Biodiversity

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

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

 

 

Production

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

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

Myrcene Diethylamine Citronellal Zinc bromide

Menthol synthesis.png

About this image

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

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

synthetic menthol production

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

References

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

 drugs, GENERIC, MANUFACTURING, nanotechnology  Comments Off on Formulation Development of Insoluble Drugs
Oct 152013
 

Formulation development of insoluble drugs has always been a challenge in pharmaceutical development. This presentation reviews some current options to old problem.

PharmaDirections, Inc.

by , Working at PharmaDirections, Inc

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