Jan 312015


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


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

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

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

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

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

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

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

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



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

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

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

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

What is API prequalification?

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

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

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

Steps in the process


The WHO prequalification procedure for medicines and active pharmaceutical ingredients


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

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

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

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

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

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

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


Maintenance of API prequalification status

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

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






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

Recovery Process:

1. Broth Filtration :

  • The main objective is to remove any microbial cells and any large solid particles such as, cell fragments, soluble and insoluble medium components, other metabolic products, Intact micro-organims.
  • During the filtration the micro-organisms are captured in a concentrated cake, which looks like sand, sludge or paste.
  • There are many factors that influence the type of filtration to be used:
    1. Viscosity.
    2. Density of filtrate.
    3. Solid liquid ratio.
    4. Size and shape of particles.
    5. Scale of operation.
    6. Need for aseptic conditions.
    7. Need for batch or continuous operation.
    8. Need for pressure or vacuum suction to ensure an sufficient for rate for liquid.
  • The rotary type is the most often used filtration, its features include:
    1. The Filter Drum: Cylindrical, hollow drum which carries the filter cloth. On the inside it is segmented into rows to which a vacuum can be applied or shut off in sequence as the drum slowly revolves.
    2. Trough: Filter is partially immersed in through which contains the penicillin broth. The trough is sometimes fitted with an agitator to maintain solids in suspension.
    3. Discharge Nodes: Filter cakes are produced from the filtration of to penicillin broth. Because of this a node is devised to scrap off the cake after filtration. When this happens the vacuum is broken.
  • The filter drum, partially submerged in the trough of broth, rotates slowly. Filtrateand washings are kept separate by the segments in the drum. The liquid is drawn throughthe filter and a cake of solids builds up on the outer surface. Inside the drum, the filtrate is moves from the end of the cylindrical drum onto a storage tank. As our penicillin cellsmove from the broth, the vacuum is used to remove as much moisture as possible fromthe cake, and to hold the cake on the drum. The section at the node/knife, which scrapes off the filtrate can get air pressure to burst out, helping contact with the node.

2. Filtrate cooled:

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

3. Further Filtration:

  • More filtration is done with rotary filtration method.

4. Extraction of Penicillin with solvent:

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

5. Carbon Treatment:

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

6. Transfer Back to Aqueous state:

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

7. Solvent Recovery:

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

8. Crystallisation:

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

9. Crystal washing:

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

10. Drying of Crystals:

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


The Whole Recovery Process in a diagram:

Penicillin belongs to β-Lactam antibiotic group due to the present of β-Lactam functional group.
The β-Lactam functional group is shown in red

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

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


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

All penicillin or penicillin derivative has a constant core region which is the 6-APA
The only region that is different from different types of penicillin derivative is its R group


Eg of derivate penicillin,

Penicillin G (most common kind of Penicillin)
Penicillin V

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

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

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


Equipments NEEDED:

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


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

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


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


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

1. Capital investments costs
2. Production costs

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The actual process flow of penicillin

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


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


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

Corn steep syrup

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

Sterilisation machine

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


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

The Penicillium fungus

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

Rotary Vacuum Filter

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

Amyl Acetate as Solvent

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

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

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

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

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

Fluid bed drying tube
Powdered penicillin being blowned by hot air

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

The White Penicillin-Sodium salt
Chemical Structure of the Penicillin Sodium Salt
Chemical Structure of the Penicillin Sodium Salt
Chemical Structure of the Penicillin Sodium Salt
Jan 262015



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


Amit B. Pawar and Sukbok Chang
Publication Date (Web): January 20, 2015 (Letter)
DOI: 10.1021/ol503680d
 A cobalt-catalyzed C–H cyanation reaction of arenes has been developed using N-cyanosuccinimide as a new electrophilic cyanating agent. The reaction proceeds with high selectivity to afford monocyanated products with excellent functional group tolerance. Substrate scope was found to be broad enough to include a wide range of heterocycles including 6-arylpurines.


Jan 242015

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

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

Graphical abstract: Synthetic chemistry fuels interdisciplinary approaches to the production of artemisinin

Synthetic chemistry fuels interdisciplinary approaches to the production of artemisinin


Corresponding authors
aDepartment of Chemistry and Biochemistry, University of California, Los Angeles, USA
Nat. Prod. Rep., 2015, Advance Article

DOI: 10.1039/C4NP00113C

Neil garg


Michael A. Corsello

Jan 242015
Expert Opin Drug Discov
Expert Opin Drug Discov 2007 Nov;2(11):1487-503
Charlotte                                                Prof Paul Watts

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

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

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

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

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

Jan 232015
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“TRIPS” redirects here. For the microprocessor, see TRIPS architecture. For the German racing driver, see Wolfgang von Trips. For other uses, see Trip.
TRIPS Agreement
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Agreement on Trade-Related Aspects of Intellectual Property Rights
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  WTO members (where the TRIPS agreement applies)
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Effective 1 January 1996
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Languages English, French and Spanish
 Agreement on Trade-Related Aspects of Intellectual Property Rights at Wikisource




The Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) is an international agreement administered by the World Trade Organization (WTO) that sets down minimum standards for many forms of intellectual property (IP) regulation as applied to nationals of other WTO Members.[2] It was negotiated at the end of the Uruguay Round of the General Agreement on Tariffs and Trade (GATT) in 1994.

The TRIPS agreement introduced intellectual property law into the international trading system for the first time and remains the most comprehensive international agreement on intellectual property to date. In 2001, developing countries, concerned that developed countries were insisting on an overly narrow reading of TRIPS, initiated a round of talks that resulted in the Doha Declaration. The Doha declaration is a WTO statement that clarifies the scope of TRIPS, stating for example that TRIPS can and should be interpreted in light of the goal “to promote access to medicines for all.”

Specifically, TRIPS requires WTO members to provide copyright rights, covering content producers including performers, producers of sound recordings and broadcasting organizations; geographical indications, including appellations of origin; industrial designs;integrated circuit layout-designspatentsnew plant varietiestrademarkstrade dress; and undisclosed or confidential information. TRIPS also specifies enforcement procedures, remedies, and dispute resolution procedures. Protection and enforcement of all intellectual property rights shall meet the objectives to contribute to the promotion of technological innovation and to the transfer and dissemination of technology, to the mutual advantage of producers and users of technological knowledge and in a manner conducive to social and economic welfare, and to a balance of rights and obligations.


Background and history

TRIPS was negotiated at the end of the Uruguay Round of the General Agreement on Tariffs and Trade (GATT) in 1994. Its inclusion was the culmination of a program of intenselobbying by the United States, supported by the European UnionJapan and other developed nations. Campaigns of unilateral economic encouragement under the Generalized System of Preferences and coercion under Section 301 of the Trade Act played an important role in defeating competing policy positions that were favored by developing countries, most notably Korea and Brazil, but also including Thailand, India and Caribbean Basin states. In turn, the United States strategy of linking trade policy to intellectual property standards can be traced back to the entrepreneurship of senior management at Pfizer in the early 1980s, who mobilized corporations in the United States and made maximizing intellectual property privileges the number one priority of trade policy in the United States (Braithwaite and Drahos, 2000, Chapter 7).

After the Uruguay round, the GATT became the basis for the establishment of the World Trade Organization. Because ratification of TRIPS is a compulsory requirement of World Trade Organization membership, any country seeking to obtain easy access to the numerous international markets opened by the World Trade Organization must enact the strict intellectual property laws mandated by TRIPS. For this reason, TRIPS is the most important multilateral instrument for the globalization of intellectual property laws. States like Russia and China [3] that were very unlikely to join the Berne Convention have found the prospect of WTO membership a powerful enticement.

Furthermore, unlike other agreements on intellectual property, TRIPS has a powerful enforcement mechanism. States can be disciplined through the WTO’s dispute settlementmechanism.

The requirements of TRIPS

TRIPS requires member states to provide strong protection for intellectual property rights. For example, under TRIPS:

  • Copyright terms must extend at least 20 years, unless based on the life of the author. (Art. 12 and 14)[4][not in citation given]
  • Copyright must be granted automatically, and not based upon any “formality,” such as registrations, as specified in the Berne Convention. (Art. 9)
  • Computer programs must be regarded as “literary works” under copyright law and receive the same terms of protection.
  • National exceptions to copyright (such as “fair use” in the United States) are constrained by the Berne three-step test
  • Patents must be granted for “inventions” in all “fields of technology” provided they meet all other patentability requirements (although exceptions for certain public interests are allowed (Art. 27.2 and 27.3)[5] and must be enforceable for at least 20 years (Art 33).
  • Exceptions to exclusive rights must be limited, provided that a normal exploitation of the work (Art. 13) and normal exploitation of the patent (Art 30) is not in conflict.
  • No unreasonable prejudice to the legitimate interests of the right holders of computer programs and patents is allowed.
  • Legitimate interests of third parties have to be taken into account by patent rights (Art 30).
  • In each state, intellectual property laws may not offer any benefits to local citizens which are not available to citizens of other TRIPS signatories under the principle of national treatment (with certain limited exceptions, Art. 3 and 5).[6] TRIPS also has a most favored nation clause.

Many of the TRIPS provisions on copyright were copied from the Berne Convention for the Protection of Literary and Artistic Works and many of its trademark and patent provisions were modeled on the Paris Convention for the Protection of Industrial Property.

Access to essential medicines[

The most visible conflict has been over AIDS drugs in Africa. Despite the role that patents have played in maintaining higher drug costs for public health programs across Africa, this controversy has not led to a revision of TRIPs. Instead, an interpretive statement, the Doha Declaration, was issued in November 2001, which indicated that TRIPs should not prevent states from dealing with public health crises. After Doha, PhRMA, the United States and to a lesser extent other developed nations began working to minimize the effect of the declaration.[7]

A 2003 agreement loosened the domestic market requirement, and allows developing countries to export to other countries where there is a national health problem as long as drugs exported are not part of a commercial or industrial policy.[8] Drugs exported under such a regime may be packaged or colored differently in order to prevent them from prejudicing markets in the developed world.

In 2003, the Bush administration also changed its position, concluding that generic treatments might in fact be a component of an effective strategy to combat HIV. Bush created the PEPFAR program, which received $15 billion from 2003–2007, and was reauthorized in 2008 for $48 billion over the next five years. Despite wavering on the issue ofcompulsory licensing, PEPFAR began to distribute generic drugs in 2004-5.

Software and business method patents

Another controversy has been over the TRIPS Article 27 requirements for patentability “in all fields of technology”, and whether or not this necessitates the granting of softwareand business method patents.

Implementation in developing countries

The obligations under TRIPS apply equally to all member states, however developing countries were allowed extra time to implement the applicable changes to their national laws, in two tiers of transition according to their level of development. The transition period for developing countries expired in 2005. The transition period for least developed countries to implement TRIPS was extended to 2013, and until 1 January 2016 for pharmaceutical patents, with the possibility of further extension.[9]

It has therefore been argued that the TRIPS standard of requiring all countries to create strict intellectual property systems will be detrimental to poorer countries’ development.[10] Many argue[who?] that it is, prima facie, in the strategic interest of most if not all underdeveloped nations to use the flexibility available in TRIPS to legislate the weakest IP laws possible.[11]

This has not happened in most cases. A 2005 report by the WHO found that many developing countries have not incorporated TRIPS flexibilities (compulsory licensing, parallel importation, limits on data protection, use of broad research and other exceptions to patentability, etc.) into their legislation to the extent authorized under Doha.[12]

This is likely caused by the lack of legal and technical expertise needed to draft legislation that implements flexibilities, which has often led to developing countries directly copying developed country IP legislation,[13] or relying on technical assistance from the World Intellectual Property Organization (WIPO), which, according to critics such as Cory Doctorow, encourages them to implement stronger intellectual property monopolies.

Banerjee and Nayak[14] shows that TRIPS has a positive effect on R&D expenditure of Indian pharmaceutical firms.

Post-TRIPS expansion

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In addition to the baseline intellectual property standards created by the TRIPS agreement, many nations have engaged in bilateral agreements to adopt a higher standard of protection. These collection of standards, known as TRIPS+ or TRIPS-Plus, can take many forms.[15] General objectives of these agreements include:

Panel reports

According to WTO 10th Anniversary, Highlights of the first decade, Annual Report 2005 page 142,[16] in the first ten years, 25 complaints have been lodged leading to the panel reports and appellate body reports on TRIPS listed below.

The WTO website has a gateway to all TRIPS disputes (including those that did not lead to panel reports) here [1].


Since TRIPS came into force it has received a growing level of criticism from developing countriesacademics, and non-governmental organizations. Some of this criticism is against the WTO as a whole, but many advocates of trade liberalization also regard TRIPS as bad policy. TRIPS’s wealth concentration effects (moving money from people in developing countries to copyright and patent owners in developed countries) and its imposition of artificial scarcity on the citizens of countries that would otherwise have had weaker intellectual property laws, are common bases for such criticisms.

Peter Drahos writes that “It was an accepted part of international commercial morality that states would design domestic intellectual property law to suit their own economic circumstances. States made sure that existing international intellectual property agreements gave them plenty of latitude to do so.”[28]

Daniele Archibugi and Andrea Filippetti[29] argue that the importance of TRIPS in the process of generation and diffusion of knowledge and innovation has been overestimated by both their supporters and their detractors. Claude Henry and Joseph E. Stiglitz[30] argue that the current intellectual property global regime may impede both innovation and dissemination, and suggest reforms to foster the global dissemination of innovation and sustainable development.

See also

Related treaties and laws

Related organizations


  1. Jump up^ “WTO TRIPS implementation”International Intellectual Property Alliance. Retrieved22 May 2012.
  2. Jump up^ See TRIPS Art. 1(3).
  3. Jump up^ Farah, Paolo Davide & Cima, Elena (2010) ‘SSRN.com China’s Participation in the World Trade Organization: Trade in Goods, Services, Intellectual Property Rights and Transparency Issues” in Aurelio Lopez-Tarruella Martinez (ed.), El comercio con China. Oportunidades empresariales, incertidumbres jurídicas, Tirant lo Blanch, Valencia (Spain) 2010, pp. 85–121. ISBN 978-84-8456-981-7.
  4. Jump up^ “intellectual property (TRIPS) – agreement text – standards”. WTO. 1994-04-15. Retrieved 2012-04-16.
  5. Jump up^ World Trade Organization“Part II — Standards concerning the availability, scope and use of Intellectual Property Rights; Sections 5 and 6″Agreement on Trade-Related Aspects of Intellectual Property Rights
  6. Jump up^ World Trade Organization“Part I — General Provisions and Basic Principles”,Agreement on Trade-Related Aspects of Intellectual Property Rights
  7. Jump up^ cf. Timmermann, Cristian, and Henk van den Belt. 2013. Intellectual property and global health: from corporate social responsibility to the access to knowledge movement. Liverpool Law Review 34 (1):47-73. also available at http://edepot.wur.nl/252885
  8. Jump up^ World Trade Organization (1 September 2003), Implementation of paragraph 6 of the Doha Declaration on the TRIPS Agreement and public health
  9. Jump up^ World Trade Organisation, IP - http://www.wto.org/english/tratop_e/trips_e/tripfq_e.htm
  10. Jump up^ IP Justice policy paper for the WIPO development agenda, IP Justice
  11. Jump up^ Trade and Health. McGill-Queen’s University Press. 2007. p. 33. |first1= missing|last1= in Authors list (help)
  12. Jump up^ Musungu, Sisule F.; Oh, Cecilia (August 2005), The use of flexibilities in TRIPS by developing countries: can they promote access to medicines?, Commission on Intellectual Property Rights, Innovation and Public Health (CIPIH)
  13. Jump up^ Finger, J. Michael (2000). “The WTO’s special burden on less developed countries”(PDF). Cato Journal 19 (3).
  14. Jump up^ Banerjee and Nayak, Effects of Trade Related Intellectual Property Rights on the R&D Expenditure of Indian Pharmaceutical Industry,2014 ‘Journal of Pharmaceutical Health Services Research.
  15. Jump up^http://www.oxfordscholarship.com/view/10.1093/acprof:oso/9780195390124.001.0001/acprof-9780195390124-chapter-8
  16. Jump up^ World Trade Organization (2005). “Annual Report 2005″.
  17. Jump up^ “2005 News items – Panel reports out on geographical indications disputes”. WTO. 2005-03-15. Retrieved 2012-04-16.
  18. Jump up^ http://www.wto.org/english/tratop_e/dispu_e/1391da.pdf
  19. Jump up^ http://www.wto.org/english/tratop_e/dispu_e/1391db.pdf
  20. Jump up^ http://www.wto.org/english/tratop_e/dispu_e/170abr_e.pdf
  21. Jump up^ http://www.wto.org/english/news_e/news00_e/1234da.pdf
  22. Jump up^ http://www.wto.org/english/news_e/news00_e/1234db.pdf
  23. Jump up^ http://www.worldtradelaw.net/reports/wtopanelsfull/canada-pharmaceuticals(panel)(full).pdf
  24. Jump up^ http://www.wto.org/english/tratop_e/dispu_e/176r_e.pdf
  25. Jump up^ http://www.wto.org/english/tratop_e/dispu_e/176abr_e.pdf
  26. Jump up^ http://www.worldtradelaw.net/reports/wtopanelsfull/india-patents(panel)(ec)(full).pdf
  27. Jump up^ http://www.worldtradelaw.net/reports/wtopanelsfull/indonesia-autos(panel)(full).pdf
  28. Jump up^ Drahos with Braithwaite, Information Feudalism, New Press 2002, p38
  29. Jump up^ Archibugi, D. and Filippetti, A. (2010) ‘The globalization of intellectual property rights: Four learned lessons and four thesis‘, Journal of Global Policy, 1: 137-49.
  30. Jump up^ Henry, C. and Stiglitz, J. (2010) ‘Intellectual Property, Dissemination of Innovation and Sustainable Development‘, Journal of Global Policy, 1: 237-51.


  • Braithwaite and Drahos, Global Business RegulationCambridge University Press, 2000
  • Westkamp, ‘TRIPS Principles, Reciprocity and the Creation of Sui-Generis-Type Intellectual Property Rights for New Forms of Technology’ [2003] 6(6) The Journal of World Intellectual Property 827-859, ISSN: 1422-2213
  • Banerjee and Nayak, ‘Effects of trade related intellectual property rights on the research and development expenditure of Indian pharmaceutical industry’ [2014] 5 Journal of Pharmaceutical Health Services Research 89-94.

External links

Jan 212015

 South Korea

KIPO logo



The Korean Intellectual Property Office (KIPO) is the patent office and intellectual property office of South Korea. In 2000, the name of the office was changed from “Korean Industrial Property Office” to “Korean Intellectual Property Office”.[1] It is located in Daejeon Metropolitan City.[2]


  1.  KIPO web site, KIPO’s history. Consulted on January 20, 2008.
  2.  KIPO web site, Contact Us. Consulted on January 20, 2008.

External links



Overview of the Patent System in Korea

KIPRIS - Korea Intellectual Property Rights Information Service
Korean Intellectual Property Office



Patent Search Websites; IP Related Organizations in Korea …


Searching in databases – Korea

Tips & tricks for searching in databases

Easy, step-by-step instructions on how to use official Korean databases. Click on the links below to download the respective search guides.

Number search and document retrieval

English machine translations

Legal status information

Searching trade marks and designs

Searching information on pharmaceutical patents

Jan 212015


The Patent Office of the Cooperation Council for the Arab States of the Gulf is delighted to announce launching the electronic filing system for patent applications “Protection” in its trial version, starting from the second of August of 2014, through the office’s official website on the internet www.gccpo.org.
The “Protection” system launch comes within the frame of the office’s comprehensi…More


The GCC Patent Office (GCCPO) is a regional patent office based in Riyadh, Saudi Arabia, within the Secretariat General of the Gulf Cooperation Council (GCC). It was established in 1992 and began operations in 1998. The GCC Patent Office grants patents valid in all GCC member states. The first GCC patent was granted in 2002. As of 2013, it employed about 30 patent examiners.[1]


Mizael Al-Harbi, Hussam Al-Muqhim (18 April 2013). “Gulf countries: introduction to the GCC patent system”. East meets West 2013. Austria.

External links


The Gulf Cooperation Council Patent Office (GCC Patent Office) is a unified patent office that serves as a convention patent office for the states of the Gulf namely, Saudi Arabia, Bahrain, Kuwait, Oman, Qatar and United Arab Emirates. The GCC Patent Office became operational in 1998. Saudi Arabia is a member of the Gulf Cooperation Council. A patent issued by the GCC Patent Office is valid and enforceable in all GCC States.

Under GCC Patent Law, it is possible to claim priority from an earlier foreign application. As compared with the Saudi Patent Office the examination process is much faster in the GCC Patent Office. Moreover, the GCC Patent Office has the following advantages:

  1. Filing a GCC Patent application will be more cost-effective than filing six separate national applications.. Therefore, by filing one application at the GCC Patent Office, protection is granted in all GCC States at a reduced cost.
  2. A Patent granted by the GCC Patent Office is valid and enforceable in all GCC States (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and U.A.E)
  3. The term of protection under GCC Patent Law is 20 years counted from the date of filing the patent application with the GCC Patent Office as opposed to 15 years as far as the other national patent laws are concerned.
  4. Duplication of registration is possible. It is possible to file a patent application in one or more of the GCC States and at the same time seek convention protection by filing at the GCC Patent Office.
  5. Compulsory Licensing under GCC Patent Law is now subjected to detailed conditions in conformity with the provision of the Trips Agreement.
  6. Importation of a patented product into GCC States will be considered as full exploitation of the invention.
  7. The GCC is taking the necessary steps to join Paris and PCT treaties in the near future.
  8. The Examination of applications is carried out by an Austrian and Australian Patent Offices.

The requirements for filing a new GCC patent application are as follows:

  1. Documents that must be filed along with the application:
    Specifications, Claims, Drawings (if any) and Abstract of the invention in English and Arabic.
  2. Documents that may be filed belatedly within 90 days from the filing date:
    1. A Power of Attorney from the applicant.
    2. An Extract from the Commercial Register or a certified copy of the Certificate of Incorporation of the applicant if the applicant is a corporate body.
    3. A Deed of Assignment, if the applicant is not the inventor.
    4. A Certified copy of the Priority document, if the applicant is claiming priority on the basis of a foreign application. Item Nos. 1,2 & 3 should be legalized up to any one of the GCC States Consulates.

Image result for saudi arabia

Industrial property is one of the branches of intellectual property. It refers to the protection of rights related to the creations of the mind applied in industrial, commercial, and agricultural fields. It covers:

• Inventions
• Industrial Designs
• Plant Varieties
• Layout Designs of integrated circuits
• Trademarks
• Geographical indications of source

King Abdulaziz City for Science and Technology (KACST) grants protection documents for inventions, layout designs of integrated circuits, plant varieties and industrial designs.

History of Industrial Property in Saudi Arabia.

In 1982, KACST was notified of the Royal Decree approving the accession of Saudi Arabia to the World Intellectual Property Organization (WIPO). Accordingly, patents has been assigned to KACST since intellectual property is essentially about patents and technology transfer and KACST is the scientific body qualified for this mission.

The first Law of Patents was issued by the Royal Decree No. (M / 38) dated 10/6/1409 H (18/1/1989 AD). The Law aimed to provide protection for inventions in Saudi Arabia, and it was modified in 19 / 7 / 1425 H (4/9/2004 AD).

The modified Law of Patents, Layout Designs of Integrated Circuits, Plant Varieties, and Industrial Designs was issued by the Royal Decree No. (M/27) dated 17/7/2004 and was published in the Official Gazette (Om Alqura) in 7/8/2004, and became effective as of 5/9/2004.

Kingdom of Saudi Arabia

المملكة العربية السعودية
Al-Mamlakah al-Arabiyah as-Sa’ūdiyah

King Abdullah of Saudi Arabia (left) and Salman bin Abdulaziz Al Saud, the Crown Prince of Saudi Arabia on the right.

Patent Application Flowchart


Desgin Application Flowchart

Saudi Arabia has ratified the Berne Convention for the Protection of Literary and Artistic Works of 1886, revised in Paris on 24th July 1971 and the Paris Convention for the Protection of Industrial Property of 1883, both with effect from 11th March 2004. Three government authorities have authority to protect and enforce intellectual property rights: the Ministry of Commerce and Industry for trademarks, the Ministry of Culture and Information for copyright, and King Abdulaziz City for Science and Technology for patents.

Trademarks are governed by the Trademarks Regulation, Royal Decree No. M/21 of 28th Jumada Awal 1423 Hejra corresponding to 8th August 2002 Gregorian, and its Implementing Rules of the same year. Applications for registration must be made to the Trademarks Office of the Ministry of Commerce and Industry which applies the ‘Nice Classification’ in accordance with the Agreement Concerning the International Classification of Goods and Services for the Purposes of the Registration of Marks of 1957.

Deera Square, central Riyadh. Known locally as “Chop-chop square”, it is the location of public beheadings.[142]

Applications must contain the following particulars:
01. A copy of the trademark required to be registered.
02. Name, title, address, nationality and trade name of the applicant (if any). If the applicant is a juristic person, the name, address of the head office and nationality must be stated.
03. Where the application is submitted by an attorney, his name, title and address must be stated.
04. Description of the trademark required to be registered.
05. The products or services in respect of which the trademark is required to be registered, and the classification thereof.
06. Signature of the applicant or the attorney thereof.
07. Ten representations of the trademark identical to the trademark sample shown in the application for registration.
08. A copy of the power of attorney together with the original for verifying purposes must be attached where the application was submitted by an attorney of the person concerned.
09. Evidence of payment of application fees as stipulated in the Trademarks Regulation.

It is not permitted to register in Saudi Arabia, by other than its rightful owner, a trademark that is similar to an internationally known mark. Registration of a trademark allows holders protection for ten years from the date of application, renewable for similar periods. Any renewal must be specifically applied for before the end of the last year of expiry of the registration, and the procedure for renewal is the same as the one for the initial registration of the trademark. Service marks are included in the definition of trademarks. A trademark is deemed owned by the person who effects the registration. Once the registration is effected in the trademarks register, the party who has registered the trademark shall be considered the owner thereof to the exclusion of others.

A trademark can be licensed, pledged or transferred by the rightful owner. The trademark may be deleted or cancelled if it is not used for five consecutive years. Penalties for infringement of a valid trademark include imprisonment for a period of not more than one year and a fine of not less than SR50,000 and not more than SR1,000,000. Any civil or criminal disputes arising from the infringement are settled by the Board of Grievances.

The Nejd landscape: desert and the Tuwaiq Escarpment near Riyadh

There are at present two overlapping patents systems in Saudi Arabia. The GCC Patents of Inventions Regulation of 2001, which is an amendment of an earlier statute of 1992, was approved in Saudi Arabia by Royal Decree No. M/28 of 2001. This permits the registration of patents with effect throughout the GCC countries. The GCC Patent Office is based in Riyadh.

Under Saudi Arabian law, patents are governed by the Layout Designs of Integrated Circuits, Plant Varieties, and Industrial Models Regulation, Royal Decree No. M/27 of 20th Jumada Awal 1425 Hejra corresponding to 17th July 2005 Gregorian, which gives effect to the Paris Convention for the Protection of Industrial Property under Saudi Arabian domestic law.

A protection document is granted by the General Directorate of Patents at King Abdulaziz City for Science and Technology, which gives full protection within the Kingdom to an invention, a layout design of an integrated circuit, a plant variety, or an industrial design. The protection document grants the owner the right to commercially exploit the subject matter of protection.

Applications for a protection document must be filed at the Directorate in the Arabic language, and must include:
01. Names and addresses of the applicant(s) and inventor(s);
02. Name and address of the local agent and the authorization, if the applicant resides outside the Kingdom;
03. A brief title of the subject matter of the application, an original copy and certified copies of the complete specification and certified copies of other relevant details thereof like examination and research reports;
04. Priority and disclosure information including previous filings; and
05. Evidence of payment of the filing fee at a designated bank, stipulated by the Directorate.
The protection document is the personal right of the owner and he may transfer or assign it or grant a contractual licence to others to commercially exploit the subject matter of protection. Protection is granted to the owner for a duration of 20 years for an invention, 10 years for an industrial design and a layout design of an integrated circuit, and 20 to 25 years for a new plant variety. The above periods are renewable, for an annual fee.

Provinces of Saudi Arabia

The Copyright Regulation, Royal Decree No. M/41 of 2nd Rajab 1424 Hejra corresponding to 30th August 2003 Gregorian and its Implementing Rules, Resolution of the Minister of Commerce and Industry No. M/W/1788/1 of 10th Rabi Thani 1425 Hejra corresponding to 30th May 2004 Gregorian, define copyright protection to include architectural designs, speeches, theatrical, musical, photographic and cinematographic works, as well as works for radio and television, maps, video tapes and computer software. Copyright protection is not subject to any registration or renewal. The Regulation gives the author financial and moral rights, to print or publish the work, to make amendments or to delete his work, to withdraw it from circulation, and to assign it as he wishes.

In general the duration of protection afforded to different types of Copyright works is as follows:
01. The period of protection of copyright for the author of a work shall be for the duration of his life and for a period of fifty years following his death.
02. The period of protection for works where the author is a corporate entity, or if the author’s name is unknown, shall be fifty years from the date of the first publication of the work.
03. The protection period for sound works, audio-visual works, films, collective works and computer programs is fifty years from the date of the first show or publication of the work, regardless of republication.
04. The protection period for applied art (handcrafted or manufactured) and photographs shall be twenty-five years from the date of publication.
05. The protection period for broadcasting organizations shall be twenty years from the date of the first transmission of program or broadcast materials.

Office of Saudi Aramco, world’s most valuable company and main source of revenue for the state.

A special Copyright Violations Committee under the authority of the Ministry of Culture and Information presides over copyright infringement issues and it has broad powers to punish the infringer of a valid copyright including a fine of up to SR250,000 in the case of first time offenders, and this can be raised to SR500,000 if there is repeated infringement. The Committee may issue injunctions in certain cases and also order imprisonment of an offender. Any decision of the Violations Committee can be appealed by filing a claim with the Board of Grievances.



Saudi Arabia is the largest and richest of the Gulf States. Its wealth derives mainly from its vast reserves of oil and natural gas, which places the country as the largest exporter of petroleum and give it a leading role in the Organization of the Petroleum Exporting Countries. It possesses about one-fifth of the world’s proven petroleum reserves. The Intellectual Property framework of Saudi Arabia has evolved to protect the different intellectual properly rights and to cope with the rapid globalization and technological change. Both globalization and technological advancement have presented significant economic opportunities and challenges to the IP system. As a result, IP rights have become increasingly important in the country, but many of the challenges facing the IP system have yet to be addressed.

The Patent Office in Saudi Arabia is located at the King Abdulaziz City for Science & Technology, an independent scientific organization of the Saudi Arabian Government established back in the year 1977. The Patent Office’s main activities and objectives are to:
(1) Apply the patent law and its implementing regulations: Law of Patents, Layout Designs of Integrated Circuits, Plant Varieties and Industrial Designs
(2) Grant Saudi patents, Layout Designs of Integrated Circuits, Plant Varieties and Industrial Designs
(3) Establish a Registry for the collection of local and foreign Layout Designs of Integrated Circuits, Plant Varieties and Industrial Designs
(4) Publish the Patents Gazette
(5) Encourage the inventiveness of Saudi nationals.
The Office has taken a number of measures during the past years to hire and train examiners and translators in order to adequately handle patent applications.

Law no. 159 on the Protection of Patents, Layout Designs of Integrated Circuits, Plant Varieties and Industrial Models.

Types of Patents
- Patents of Invention
- Divisional Patents

Priority Claim
Saudi Arabia is a member of the Paris Convention. Applicants can benefit from a right of priority of 12 months to file a corresponding Saudi patent application.

Patent Cooperation Treaty
Saudi Arabia has joined the PCT but still the entry of national phase of PCT application is not possible as the relevant regulations and laws have not been issued, we expect the implementation of PCT within next 6-12 months.

The Mosque of the Prophet in Medina containing the tomb of Muhammad.

Definition of an Invention
An invention must be novel, involves an inventive step and capable of industrial application. The invention may be a product, an industrial process or relates to either (Article 43).

Types of Claims
Product and process claims are acceptable. When a patent is granted for a process, any product made directly by such a process is also protected (Article 47(b)).

Exception to Protection
An invention is not patentable if it is: a discovery; a scientific theory or mathematical method; an aesthetic creation such as a literary, dramatic, or artistic work; a scheme or method for performing a mental act, games or business methods; the presentation of information; or a computer program.

- Novelty:
the invention must never have been made public in any way, anywhere in the world, before the filing date or the priority date.
- Inventiveness: an invention involves an inventive step if, when compared with what is already known, it would not be obvious to someone skilled in the relevant field.
- Industrial applicability: an invention must be capable of being made or used in some kind of industry.

Laboratory buildings at KAUST

Absolute novelty is required. Any act that makes an invention available to the public before the filing date or priority date has the effect of barring the invention from being patented in Saudi Arabia (Absolute Novelty). Examples of acts that can make an invention available to the public are publications, sales, public oral disclosures and public demonstrations or use, etc. However, the patent application can still be filed if disclosure was very limited and can not be cited by the examiner. Also, a one year grace period is available if the disclosure of the invention was proven to be made without the knowledge or consent of the inventor (Article 44).  Wrong statement article 44 if disclosed within the priority period, but the exception is under article 30 of Implementing Regulations where the grace period is 6 months if the disclosure occurred because of abusive action.

Application Workflow
A formal examination is conducted first. If application fails to meet all the set requirements, the applicant will be notified and will be given a period of 90 days to complete the application. Once completed, the application will proceed to substantive examination. The examiner will assess the application for patentability (novelty and industrial applicability). If the claimed invention is not patentable, the applicant will be requested to present counter-arguments within 90 days from notification date. If the claimed invention is patentable, the applicant will be requested to settle the grant and publication fees. Accordingly, the letters patent will be issued and the decisions to grant the patent will be published in the Patent Official Gazette for opposition purposes.

Oppositions may be filed within 90 days from publication date before the Board of Grievances.

Protection Term
The term of protection is 20 years from filing date.

A maintenance fee is due annually on patents and is payable the first 3 months of each calendar year following the year the patent application was filed. There is a 3-month grace period for late payment with a surcharge.

Compulsory Licensing
A patent has to be worked. If the patent is not being fully exploited by the patentee within 4 years from the date of filing or 3 years from the date of grant, the patent will be subject to compulsory licensing under the provisions of the law.
Naming of the Inventor on the Letters Patent

Ibn Saud, the first king of Saudi Arabia

Employer and Employee’s Rights
Employer’s Rights
The employer shall be the patentee
(1) if the invention is made in execution of a contract or a commitment for the execution of inventive efforts, unless the work contract stipulates otherwise, or
(2) if the employee would not have developed the subject matter of the protection had he not used facilities, means or data made available through his employment
Employee’s Rights
The employee has the right to receive a remuneration to be agreed upon with the consent of both parties or assessed in light of the various circumstances of the contract of employment and the economic importance of the subject matter of the protection. Any special agreement depriving the employee of this right shall be null and void.
General Provisions
A patent application filed by the employee within two years from the date of termination of employment will be considered as if submitted during employment.
All previous provisions will apply to government employees.

Patent Linkage
Requests for marketing approval of generic drugs must include details on the corresponding patent if available (filing no., filing date, and country of grant). The SFDA will then contact the Saudi Patent Office to confirm whether a patent is involved before giving marketing approval. The GCC Patent Office is not usually contacted.

Filing Requirements
1. Power of attorney, legalized up to the Saudi Consulate
2. 2 copies of the specifications in English with Arabic translation
3. 2 sets of drawings in Arabic and one in English.
4. Deed of assignment from the inventor(s), legalized up to the Saudi Consulate
5. Copy of priority document, if priority is claimed, certified.
Item 3 must be submitted at the time of filing. Document 5 must be submitted within 12 months from priority date.
Documents 1 and 4 may be submitted within 1 month from filing date.

Verses from the Quran. The Quran is the official constitution of the country and a primary source of law. Saudi Arabia is unique in enshrining a religious text as a political document[130]

GCC Protection
Patent protection in Saudi Arabia can also be obtained through the Gulf Cooperation Council unified patent registration system (GCC patent law of 1999).

2011 Figures
Saudi Arabia ranked first among the Arab countries in the number of patents granted for the year 2011 which amounted to 147, based on WIPO sources. It also ranked first in the number of patents filed in the same year which amounted to 78.

FAQ – Saudi Arabia (SA)


For more specific legal questions relating to the Saudi Arabian patent system, please contact International_legal_affairs@epo.org.


General information about IP in Saudi Arabia

From filing to grant

After grant

Sources of information

Supplicating pilgrim at Masjid Al Haram, Mecca


General information about IP in Saudi Arabia

How to protect an invention in Saudi Arabia

There are two options for protecting an invention on Saudi Arabian territory:

  1. The first option is to file a patent application with the Saudi Arabian Patent Office. If a patent is granted, the invention will be protected only in Saudi Arabia.
  2. The second option is to file a patent application with the Gulf Cooperation Council (GCC) Patent Office. The GCC is a regional organisation comprising six Arab countries: the Kingdom of Saudi Arabia, Qatar, Kuwait, the United Arab Emirates, the Sultanate of Oman, and Bahrain. The GCC Patent Office is a regional office that registers patents in the member states of the GCC. Patents granted by the GCC Patent Office are valid in all GCC member states.

GCC Patent Office website

All the information presented below relates to the first option, protection via the Saudi Arabian Patent Office.


What types of industrial property rights exist in Saudi Arabia?

Saudi Arabia has patents, plant varieties, industrial designs, layout designs of integrated circuits and trade marks, but not utility models. Patents and designs can be registered at the Saudi Arabian Patent Office (official name: General Directorate of Patents at King Abdulaziz City of Science and Technology (KACST)). Trade marks can be registered at the Ministry of Commerce and Industry.


How long are the terms of protection of Saudi Arabian intellectual property rights?

The terms of protection for the different types of intellectual property are as follows:

  • patents: 20 years from the date of filing
  • plant varieties: 20 years
  • industrial designs: 10 years
  • layout designs of integrated circuits: 10 years


When may a patent not be granted?

Article 4 of the Saudi Arabian Patent Law states the following:

“(a) The protection document shall not be granted if its commercial exploitation violates the Shari’ah (Islamic law).

(b) The protection document shall not be granted if its commercial exploitation is harmful to life, to human, animal or plant health, or is substantially harmful to the environment.”


What inventions cannot be patented in Saudi Arabia?

Article 45 of the Saudi Arabian Patent Law states the following:

“In the application of provisions of this Law, the following shall not be regarded as inventions:

(a) Discoveries, scientific theories and mathematical methods.

(b) Schemes, rules and methods of conducting commercial activities, exercising pure mental activities or playing a game.

(c) Plants, animals and processes – which are mostly biological – used for the production of plants or animals, with the exception of micro-organisms, non-biological and microbiology processes.

(d) Methods of surgical or therapeutic treatment of human or animal body and methods of diagnosis applied to human or animal bodies, with the exception of products used in any of these methods.”

The exclusion also applies to computer programs and any other copyright work.

Laws & Regulations


Can computer software be patented in Saudi Arabia?

Computer programs as such are not patentable, but may be protected by copyright. Computer-related inventions may be patentable in Saudi Arabia if the requirements for patentability are met.

Laws & Regulations


Is Saudi Arabia a member of the Patent Cooperation Treaty (PCT)?

As of 3 August 2013, Saudi Arabia will be bound by the PCT. From that date onwards, nationals and residents of Saudi Arabia will be entitled to file international applications under the PCT.


From filing to grant

As a foreign applicant, do I need to appoint a professional representative in Saudi Arabia?

All non-residents wishing to apply for a patent require an authorised Saudi Arabian representative. Applicants have to file a power of attorney which has been duly notarised and legalised by the consulate of Saudi Arabia.

More information:

Professional representative


What language must I use for a patent application in Saudi Arabia?

Documents submitted under the Saudi Arabian Law of Patents must be in Arabic.

Can I claim priority for an application filed in Saudi Arabia?

Yes, the priority term is 12 months from the earliest claimed priority, as stipulated in the Paris Convention. Saudi Arabia has been a member of the Paris Convention since 2004.


What do I need to do to get an early filing date in Saudi Arabia?

Does Saudi Arabia allow divisional applications?

Yes. Where an application contains two or more inventions, applicants may submit a divisional application on their own initiative any time before the decision to grant or reject the application.


Do I have to file a request for examination (“deferred examination”) in Saudi Arabia?

You do not need to file a request for examination. Applications are examined automatically, on the basis of the filing date. It is possible to withdraw applications.


Can I withdraw my application before it is published in Saudi Arabia?

Yes, you can withdraw an application before it is published.


Can I request that my application in Saudi Arabia be published earlier than 18 months from the filing (or earliest priority) date?

No, it is not possible to request early publication of an application.


Can I submit third-party observations on a Saudi Arabian patent application?

No, it is not possible to submit third-party observations.

King Abdullah Economic City

What is the time limit for responding to official actions in Saudi Arabia?

Responses to official actions should be submitted within 90 days from the date of the action.


After grant

When do I have to pay annual fees in Saudi Arabia?

Annual fees are due at the beginning of each year (1 January until 30 March), starting from the year following the filing date.


Is there a grace period for paying annual fees in Saudi Arabia?

Applicants or patent holders who fail to pay within a maximum period of three months from the due date are liable to pay double the amount of the fee. If they fail to pay after being warned during the three months following the expiration of the first three months, the patent will cease to be valid and this will be recorded in the Register and published in the Gazette.


Can a lapsed patent be restored in Saudi Arabia?

In case of force majeure it is possible to have a lapsed patent restored at the Saudi Arabian Patent Office.


Makkah in Saudi Arabia

Can I request an extension of the patent term in Saudi Arabia?

No. In Saudi Arabia the 20-year term for patents cannot be extended. The Saudi Arabian Patent Law does not include any provisions on patent term extensions or supplementary protection certificates (SPCs).


How can I challenge a granted patent in Saudi Arabia?

Within 90 days from publication of the decision to grant, any interested party may apply for partial or total revocation of the patent.

Invalidation is possible for a third party at any time after grant and must be raised before a separate governmental body (Appeals Committee).


Sources of information

Where can I search Saudi Arabian patent information in English?

The Saudi Arabian Patent Office has an English-language database known as “IP search”. On this platform you can perform searches according to dates, numbers or applicant/inventor names.

IP Search

If you require a more detailed answer, please send us your question using the contact form.

Where can I find English abstracts of Saudi Arabian patent documents?

In general, the Saudi Arabian Patent Office does not produce any English abstracts for its patent documents. Where a non-Saudi Arabian applicant files an application, the abstract may also be in English (and in Arabic), while the rest of the patent has to be in Arabic only. Therefore, English abstracts are also available in certain circumstances.


Where can I get an English machine translation of a Saudi Arabian patent?

There are no machine translations of Saudi Arabian patents available yet.


Where can I find legal-status information on Saudi Arabian patents in English?

In general, legal-status information for Saudi Arabian patents is not yet available, but a brief “application status” can be found together with the bibliographic information in the “IP search” database.


Where can I find official information about fees in Saudi Arabia?

Information about fees is currently available in Arabic only.

Schedule of fees


Where can I find information about patent agents in Saudi Arabia?

The KACST website gives detailed information about the role of patent attorneys and the services they provide. It is available in Arabic only.

Professional representative

If you require a more detailed answer, please send us your question using the contact form.

Jan 182015

Skeletal formula


Ball-and-stick model

Methohexital or methohexitone, (marketed under the brand name Brevital) is a drug which is a barbiturate derivative. It is classified as short-acting, and has a rapid onset of action. It is similar in its effects to sodium thiopental, a drug with which it competed in the market for anaesthetics.



Methohexital binds to a distinct site which is associated with Cl ionophores at GABAA receptors.[1] This increases the length of time which the Cl ionopores are open, thus causing an inhibitory effect.

Metabolism of methohexital is primarily hepatic (i.e., taking place in the liver) via demethylation and oxidation.Side-chain oxidation is the primary means of metabolism involved in the termination of the drug’s biological activity.

Protein binding is approximately 73% for methohexital.


Methohexital is primarily used to induce anesthesia, and is generally provided as a sodium salt (i.e. methohexital sodium). It is only used in hospital or similar settings, under strict supervision.[citation needed] It has been commonly used to induce deep sedation or general anesthesia for surgery and dental procedures. Unlike many other barbiturates, Methohexital actually lowers the seizure threshold, a property that make it particularly useful when anesthesia is provided for a electroconvulsive therapy (ECT). And rapid recovery rate with consciousness being gained within three to seven minutes after induction and full recovery within 30 minuntes is a major advantage over other ECT barbiturates (Schulgasser and Borowitz 1963).


Methohexital, 5-allyl-1-methyl-5-(1-methyl-2-pentinyl barbituric acid, is synthesized in the classic manner of making barbituric acid derivatives, in particular by the reaction of malonic ester derivatives with derivatives of urea.

Methohexital synthesis: W.J. Doran, U.S. Patent 2,872,448 (1959).

The resulting allyl-(1-methyl-2-pentynyl) malonic ester is synthesized by subsequent alkylation of the malonic ester itself, beginning with 2-bromo-3-hexyne, which gives (1-methyl-2-pentynyl)malonic ester, and then by allylbromide. In the final step, reaction of the disubstituted malonic ester with N-methylurea gives desired methohexital.

Skeletal formula
Ball-and-stick model
Systematic (IUPAC) name
5-hex-3-yn-2-yl-1- methyl-5-prop-2-enyl-1, 3-diazinane-2,4,6-trione
Clinical data
AHFS/Drugs.com Consumer Drug Information
Legal status
Routes Intravenous, rectal
Pharmacokinetic data
Bioavailability I.V. ~100%
Rectal ~17%
Metabolism Hepatic
Half-life 5.6 ± 2.7 minutes
Excretion ?
CAS number 151-83-7 Yes
ATC code N01AF01 N05CA15
PubChem CID 9034
DrugBank DB00474
ChemSpider 8683 Yes
KEGG D04985 Yes
ChEBI CHEBI:102216 Yes
Chemical data
Formula C14H18N2O3 
Molecular mass 262.304



  1. Katzung, Bertram G., Basic and Clinical Pharmacology, 10th ed., p. 406-407


External links


Jan 142015


Scaling from Milligrams to 1-2Kg

see at…………..http://news.scientificupdate.co.uk/index.php?action=social&chash=1c1d4df596d01da60385f0bb17a4a9e0.1201

2 – 3 March 2015
Sheraton Fisherman’s Wharf Hotel - San Francisco


Fisherman's Wharf, San Francisco

The aim of this professional development course is to provide a good basis to work from when involved in taking development candidates to the first in human trials and with a view on some longer-term requirements. The course content will focus on the necessary early phases of chemical development, as would typically be required to support production of up to about 2kg.

The course will introduce and discuss the following:

  • Requirements in order to move from small (less than 1g) supplies to the first 100g or so for preclinical work
  • Further scaling to 1-2kg non-cGMP
  • Requirements to make material for use in clinical trial – an introduction to cGMP coupled with the scaling issues
  • An overview of the requirements to move processes to fixed vessels, assuming cGMP is required – what operations can readily be transferred and those that should ideally be developed out
  • The phases of development and indicative timelines with quality requirements
  • The importance of physical form selection, understanding and control
  • Impurities and their control, with specific discussion on genotoxic impurities and developing the specification for the API as it moves from preclinical batch preparation to cGMP batches for clinical trials

Your Course Tutor
Dr John Knight 

John Knight

Register 2 attendees and automatically SAVE 5% plus register 3 people and SAVE 15% on our standard booking fees!


sciupnew logo-master

Who should attend…

  • Project managers and those involved in technical outsourcing
  • Project leaders and bench chemists involved in preparation of material
  • New starters to the area
  • Medicinal Chemistry support teams involved in making the first batches for toxicological evaluation

What will you take away from this course…

  • How long it takes to get from milligrams to 1-2kgs suitable for human clinical trials
  • What are the main hurdles
  • What can be left out and what must be included
  • What are the key project management considerations

View the course brochure

The lectures are interspersed with interactive problem sessions.

see http://news.scientificupdate.co.uk/index.php?action=social&chash=1c1d4df596d01da60385f0bb17a4a9e0.1201

Copyright © 2015 Scientific Update LLP, All rights reserved.
Scientific Update LLP, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, UK
T: +44 (0)1435 873062 F: +44 (0)1435 872734 E. info@scientificupdate.co.uk

missing link

OPRD network

Jan 082015






(R)-(+)-R 115777; Zarnestra; 192185-68-5

zarnestra, 192185-72-1, R115777, R-115777, IND 58359, UNII-MAT637500A

192185-72-1, 192185-68-5

Molecular Formula: C27H22Cl2N4O
Molecular Weight: 489.39578 g/mol
192185-72-1, 192185-68-5 (racemate), 192185-70-9 (racemic; diHCl), 192185-69-6 (racemic; fumarate)
R115777 is a substance that is being studied in the treatment of acute myeloid leukemia (AML) and other types of cancer. It belongs to the family of drugs called farnesyltransferase inhibitors. It is also called tipifarnib and Zarnestra.

Tipifarnib (trade name Zarnestra) is a farnesyltransferase inhibitor that is being investigated in patients 65 years of age and older with newly diagnosed acute myeloid leukemia (AML). It inhibits the Ras kinase in a post translational modification step before the kinase pathway becomes hyperactive. It inhibits prenylation of the CxxX tail motif, which allows Ras to bind to the membrane where it is active. Without this step the protein cannot function.

It is also being tested in clinical trials in patients in certain stages of breast cancer.[1]

For treatment of progressive plexiform neurofibromas associated with Neurofibromatosis type I, it successfully passed phase one clinical trials but was suspended (NCT00029354) in phase two.[2][3] The compound was discovered by and is under investigation byJohnson & Johnson Pharmaceutical Research & Development, L.L.C, with registration number R115777.

Approval process

Tipifarnib was submitted to the FDA by Johnson & Johnson for the treatment of AML in patients aged 65 and over with a New Drug Application (NDA) to the Food and Drug Administration (FDA) on January 24, 2005.

In June 2005, the FDA issued a “not approvable” letter for tipifarnib.[4]

Farnesyltransferase inhibitors block the main post-translational modification of the Ras protein, thus interfering with its localization to the inner surface of the plasma membrane and subsequent activation of the downstream effectors. Although initially developed as a strategy to target Ras in cancer, farnesyltransferase inhibitors have subsequently been acknowledged as acting by additional and more complex mechanisms that may extend beyond Ras involving GTP-binding proteins, kinases, centromere-binding proteins and probably other farnesylated proteins.

A particular farnesyltransferase inhibitor is described in WO 97/21701, namely (R)-(+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone. The absolute stereochemical configuration of the compound was not determined in the experiments described in the above-mentioned patent specification, but the compound was identified by the prefix “(B)” to indicate that it was the second compound isolated from column chromatography. The compound thus obtained has been found to have the (R)-(+)-configuration. This compound will be referred to below by its published code number R115777 and has the following formula (V).


Figure US07572916-20090811-C00002


R115777 (Tipifarnib) is a potent, orally active inhibitor of farnesylprotein transferase. It is one of the most advanced of the farnesylprotein transferase inhibitors currently reported to be in clinical development, being one of the agents that have progressed to phase III studies.

R115777 has been found to have very potent activity against neoplastic diseases. Antineoplastic activity in solid tumors, such as breast cancer, as well as in haematological malignancies, such as leukemia, have been observed. Also combination studies have been carried out demonstrating that R115777 can be safely combined with several highly active anticancer drugs.

In WO 01/53289, the racemates (±) (4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-(4-methoxy-benzylamino)-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (racemate 1) and (±) 4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-[(4-methoxy-benzylidene)-amino]-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (racemate 2) are prepared.


Figure US07572916-20090811-C00003


After chiral molecule separation using column chromatography, either the benzylamino or the benzilidine moiety of the resulting (+) and/or (−) enantiomers are converted to an amino group under acidic conditions.

In WO 97/21701, it is described (on page 9, line 7-14) that intermediates of formula (XIII), can be prepared by reacting an intermediate of formula (XIV), wherein W is an appropriate leaving group, such as, for example, halo, with an intermediate ketone of formula (XV). In WO 97/21701, it is described that this reaction can be performed by converting the intermediate of formula (XV) into an organometallic compound, by stirring it with a strong base such as butyl lithium and subsequently adding the intermediate ketone of formula (XV). It is further indicated that although this reaction gives at first instance a hydroxy derivative (i.e. Ris hydroxy), said hydroxy derivative can be converted into other intermediates wherein Rhas another definition by performing art-known (functional group) transformations. The drawings of the compounds of formula (XIII), (XV) and (XIV) have been taken over from WO 97/21701 and the substituents in these drawings are as defined in WO 97/21701.


Figure US07572916-20090811-C00004


In WO 97/21701, it is also described (from page 7 line 32, to page 8 line 6) that the compounds of formula (XVI), wherein R is C1-6alkyl, R(2-8, 16-19) can be a substituent chosen from lists as defined in WO 97/21701 and Rhas a meaning as defined in WO 97/21701 apart from hydrogen, may be prepared by hydrolysing an intermediate ether of formula (XIII), according to art-known methods, such as stirring the intermediate of formula (XIII) in an aqueous acid solution. An appropriate acid can be for instance hydrochloric acid. Subsequently the resulting quinolinone, wherein Ris hydrogen, may be transformed into a quinolinone of formula (XVI) by art-known N-alkylation. The drawings of the compounds of formula (XIII) and (XVI) have been taken over from WO 97/21701 and the substituents in these drawings are as defined in WO 97/21701.


Figure US07572916-20090811-C00005


The synthesis of R115777 as originally described in WO 97/21701, is presented in scheme 1.

Herein, in step 1, the intermediate 1-methyl imidazole in tetrahydrofuran, is mixed with a solution of n-butyllithium in a hexane solvent to which is added chlorotriethylsilane (triethylsilyl chloride), followed by a further addition of n-butyllithium in hexane, the resulting mixture being cooled to −78° C. before the addition of a solution of a compound of formula (I), i.e. 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone in tetrahydrofuran. The reaction mixture is subsequently brought to room temperature, and then hydrolysed, extracted with ethyl acetate and the organic layer worked up to obtain a compound of formula (II), i.e. (±)-6-[hydroxy(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone.

In step 2, the hydroxy compound of formula (II) is chlorinated with thionylchloride to form a compound of formula (III), i.e. (±)-6-[chloro(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone.

In step 3, the chloro compound of formula (III) is treated, with NH4OH in tetrahydrofuran to form the amino compound of formula (IV), i.e. (±)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone.

In step 4, the amino compound of formula (IV) is separated into its enantiomers by chiral column chromatography over Chiracel OD (25 cm; eluent: 100% ethanol; flow: 0.5 ml/min; wavelength: 220 nm). The pure (B)-fractions are collected and recrystallised from 2-propanol resulting in R115777, the compound of formula (V).


Figure US07572916-20090811-C00006


However, the procedure described in WO97/21701 has a number of disadvantages. For example, during the first step, the procedure results in the undesired formation of a corresponding compound of formula (XI), i.e. 6-[hydroxy(4-chlorophenyl)(1-methyl-1H-imidazol-2-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone), in which the imidazole ring is attached to the remainder of the molecule at the 2-position of the ring, instead of the desired 5-position. At the end of the procedure, this results in the formation of a compound of formula (XII), i.e. 6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-2-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone.


Figure US07572916-20090811-C00007


Furthermore, the purification of compound (V) using chiral chromatography is expensive and disadvantageous in view of the large amounts of solvent needed and the specialised equipment required to perform a large scale chiral chromatography.

Another process for the synthesis of R115777 as described in WO 02/072574, is presented in scheme 2.

Herein, in step 1, 1-methyl imidazole in tetrahydrofuran is mixed with a solution of n-hexyllithium in a hexane solvent to which is added tri-iso-butylsilyl chloride, followed by a further addition of n-hexyllithium in hexane. The compound of formula (I) in tetrahydrofuran is then added to the reaction mixture, keeping the temperature between −5° C. and 0° C. The resulting product of formula (II) is isolated by salt formation.

In step 2, the chlorination reaction is effected by treatment of the compound of formula (II) with thionyl chloride in 1,3-dimethyl-2-imidazolidinone.

In step 3, the chloro compound of formula (III) is treated with a solution of ammonia in methanol. After the addition of water, the compound of formula (IV), precipitates and can be isolated.

In step 4, the compound of formula (IV) can be reacted with L-(−)-dibenzoyl tartaric acid (DBTA) to form the diastereomeric tartrate salt with formula (VI) i.e. R-(−)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone [R—(R*,R*)]-2,3-bis(benzoyloxy)butanedioate (2:3).

Finally, in step 5, the compound of formula (VI) is treated with aqueous ammonium hydroxide, to form the crude compound of formula (V) which is then purified by recrystallisation from ethanol to the pure compound (V).


Figure US07572916-20090811-C00008
PatentSubmittedGrantedNOVEL IV FORMULATION OF TIPIFARNIB [US2009042935]2009-02-12
Novel IV formulation of tipifarnib [US2007093449]2007-04-26
Medical devices to treat or inhibit restenosis [US2005154451]2005-07-14
Patent Submitted Granted
Process for the preparation of imidazole compounds [US6844439] 2004-07-15 2005-01-18
Diastereoselective Synthesis Process with 6-Bromo-4-(3-Chlorophenyl)-2-Methoxy-Quinoline [US7572916] 2007-12-20 2009-08-11
Anti-cancer phosphonate analogs [US7452901] 2006-04-13 2008-11-18
Diastereoselective Synthesis Process for the Preparation of Imidazole Compounds [US7456287] 2007-10-11 2008-11-25
Diastereoselective Addition of Lithiated N-Methylimidazole on Sulfinimines [US7524961] 2007-12-20 2009-04-28
Therapeutic phosphonate compounds [US7645747] 2006-11-23 2010-01-12
EXAMPLE A.1 a) Preparation of N-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methylene)]-2-methyl-2-propanesulfinamide [(S(R)] (Compound 25)

Figure US07572916-20090811-C00019


Ti(OEt)(0.0162 mol) was added to a mixture of (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (0.0032 mol) and (R)-(+)-2-methyl-2-propane-sulfinamide (0.0032 mol) in DCE (7 ml). The mixture was stirred and refluxed for 6 days, then cooled to room temperature. Ice water was added. The mixture was filtered over celite. Celite was washed with DCM. The organic layer was extracted with saturated sodium chloride. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. This fraction was purified by column chromatography over silica gel (40 μm) (eluent: DCM/MeOH/NH4OH 97/3/0.5), yielding 0.475 g of compound 25 (46%).

The compound N-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methylene)]-2-methyl-2-propanesulfinamide [(S(S)] can be obtained in an analogous way.

b) Preparation of N-[(4-chlorophenyl)((4-(3-chlorophenyl)-2-methoxy-quinoline-6-yl)(1-methyl-1H-imidazole-5-yl)methyl]-2-methyl-2-propanesulfinamide [S(R)] (Compound 26)

Figure US07572916-20090811-C00020


n-Butyllithium (0.00081 mol) in hexane, was added dropwise at −78° C. to a mixture of 6-bromo-4-(3-chlorophenyl)-2-methoxy-quinoline (0.00081 mol) in THF (3 ml) under nitrogen flow. The mixture was stirred at −78° C. for 30 minutes. A solution of compound 25 (0.00065 mol) in THF (0.6 ml) was added. The mixture was stirred at −78° C. for 1 hour and 30 minutes, poured out into ice water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. This fraction was purified by column chromatography over silica gel (40 μm)(eluent: DCM/MeOH/NH4OH 97/3/0.1). The pure fractions were collected and the solvent was evaporated, yielding 0.138 g (36%) of compound 26, melting point 153° C.

The compound N-[(4-chlorophenyl)((4-(3-chlorophenyl)-2-methoxy-quinoline-6-yl)(1-methyl-1H-imidazole-5-yl)methyl]-2-methyl-2-propanesulfinamide [S(S)] can be obtained in an analogous way

c) Preparation of (S)-1-(4-chlorophenyl)-1-[4-(3-chlorophenyl)-2-methoxy-quinoline-6-yl]-1-(1-methyl-1H-imidazole-5-yl)-methylamine (Compound 27)

Figure US07572916-20090811-C00021


Hydrochloric acid in isopropanol was added to a solution of compound 26 (0.000018 mol) in methanol (4.2 ml). The mixture was stirred at room temperature for 30 minutes. The mixture was added to potassium carbonate (10%) on ice and extracted with ethyl acetate. The organic layer was separated, washed with a solution of saturated sodium chloride, dried (MgSO4), filtered, and evaporated giving 0.086 g (100%) of compound 27, melting point 96° C., enantiomeric excess 88%.

d) Preparation of (S)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1H)-quinolin-2-one (Compound 28)

Figure US07572916-20090811-C00022


Compound 27 (0.00038 mol) in hydrochloric acid 3N (9.25 ml) and THF (9.25 ml), was stirred at 60° C. for 24 hours and evaporated, giving 0.18 g (100%) of compound 28, melting point 210° C.

EXAMPLE A.2 a) Preparation of N-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methylene)]-p-toluenesulfinamide [(S(S)](Compound 29)

Figure US07572916-20090811-C00023


Ti(OEt)(0.0419 mol) was added to a mixture of (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (0.0084 mol) and (S)-(+)-p-toluenesulfinamide (0.0084 mol) in DCE (18 ml). The mixture was stirred and refluxed for 7 days, then cooled to room temperature. Ice water was added. The mixture was filtered over celite. Celite was washed with DCM. The organic layer was extracted with saturated sodium chloride. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. This fraction was purified by column chromatography over silica gel (40 μm) (eluent: DCM/MeOH/NH4OH 97/3/0.5), yielding 1.15 g of compound 29 (38%).

The compound N-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methylene)]-p-toluenesulfinamide [(S(R)] can be obtained in an analogues way.

B. Preparation of Final Compounds

EXAMPLE B.1 a) Preparation of (S)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (Compound 30)

Figure US07572916-20090811-C00024


Compound 28 (0.00038 mol) was added to a solution of THF (1.8 ml) and NaOH 10N (1.8 ml). BTEAC (0.0019 mol) and methyliodide (0.00076 mol) were added and the mixture was stirred for 2 hours at room temperature. EtOAc was added. The organic layer was separated, dried (MgSO4), filtered, and evaporated giving 0.149 g (83%) of compound 30, enantiomeric excess 86%.

Cyclization of 3- (3-chlorophenyl) -N-phenyl-2-propenamide (I) by means of polyphosphoric acid (PPA) at 100 C gives 4- (3-chlorophenyl) -1,2,3,4-tetrahydroquinolin- 2-one (II), which is condensed with 4-chlorobenzoic acid (III) by means of PPA at 140 C to yield 6- (4-chlorobenzoyl) -4- (3-chlorophenyl) -1,2,3,4 -tetrahydroquinolin-2-one (IV). The dehydrogenation of (IV) by means of Br2 in bromobenzene at 160 C affords 6- (4-chlorobenzoyl) -4- (3-chlorophenyl) quinolin-2 (1H) -one ( V), which is methylated with iodomethane and NaOH / benzyltrimethylammonium chloride in THF to provide 6- (4-chlorobenzoyl) -4- (3-chlorophenyl) -1-methylquinolin-2 (1H) -one (VI). Condensation of compound (VI) with 1-methylimidazole (VII) by means of butyllithium in THF gives the triaryl carbinol (VIII), which is finally treated with ammonia in THF to afford R-115777.
Org. Lett., Article ASAP
DOI: 10.1021/ol503292p
Abstract ImageQuinolinone derivatives were constructed via a Pd-catalyzed C–H bond activation/C–C bond formation/cyclization cascade process with simple anilines as the substrates. This finding provides a practical procedure for the synthesis of quinolinone-containing alkaloids and drug molecules. The utility of this method was demonstrated by a formal synthesis of Tipifarnib.


  1.  [1]
  2.  “R115777 in Treating Patients With Advanced Solid Tumors”
  3.  “R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas”
  4.  R115777 New Drug Application

Angibaud, P.; Venet, M.; Filliers, W.; Broeckx, R.; Ligny, Y.; Muller, P.;Poncelet, V.; End, D. Eur. J. Org. Chem. 2004, 479.


(b) Filliers, W.; Broeckx, R.;Angibaud, P. U.S. patent, US7572916, 2009.


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