Case Studies and Experience

Project Objective: Provide synthesis services and med-chem consulting on a novel non-alkaloid analgesic.

Discussion: Starting with a plant-derived natural product, a hit optimization study was completed resulting in over a 10000 fold improvement in the receptor binding affinity of the target scaffold.  Several iterations of pharmacophores, synthesis and testing led to a group of leads that are currently undergoing further in-vitro and in-vivo testing.  Apertus aided in design and route selection then provided all synthesis services, and scale up for testing.

Outcome: A first round of hit optimization led to a substantial increase in target receptor affinity.  Over 50 compounds were synthesized, isolated and tested.

Patent pending.

Project Objective: Alkaloid extract contains unknown impurity at levels above 1%. Identify and reduce impurity.

Description:  Extraction of poppy straw had an unknown impurity that was at levels above 1% by HPLC in about 20% of the extracts.  Using prep chromatography, LC-MS and NMR, the impurity was isolated and identified.  Trend charts showed a correlation to pH and the impurity’s levels in the drug substance.

Outcome:  The manufacturing process was modified to remove or lower the levels of the impurity.  Isolation and identification led to a relative response factor for HPLC analysis.  The failure rate of this step was improved from 20% to 5%.

Project Objective: Reduce alpha-beta unsaturated ketones (ABUKs) in oxymorphone and oxycodone.

Discussion: A variety of methods exist to reduce ABUKs in oxycodone and oxymorphone.  A novel method developed in-house was found to reduce the ABUK levels to nearly undetectable amounts by single ion monitoring mass spectrometry. The method involved isolation of an intermediate that was efficiently hydrogenated to the target API followed by a workup that proved efficient at removing traces of ABUK. In addition, the isolated products were bright white solids.

Outcome: A novel method to reduce ABUKs in oxymorphone and oxycodone was developed that yielded white, low ABUK product.

Patent pending.

Project Objective:  Determine dimer impurity in acid chloride raw material that carried through into finished API

Description: A synthetic drug product contained an impurity that was theorized to be from a raw material contamination.  The acid halide raw material is not tested due to air reactivity and respiratory concerns to the analyst and sampler.  A gas chromatography method was developed that detected potential water contamination, as well as dimers.  The procedure used sample containment techniques to reduce sampler and analyst exposer as well as prevent air introduction to the sample.  The procedure was validated and transferred to the quality control group.

Outcome: A gas chromatography method was developed and validated for testing a noxious raw material and its impurities.  This procedure also certified the material past its retest date.  Samplers and analysts were trained on handling the acid halide raw material.  The chromatography procedure was successfully transferred to quality control personnel.

Project Objective: Design a novel catalyst for the conversion of morphine to hydromorphone.

Discussion: Several examples of the catalytic conversion of morphine to hydromorphone are available but most use one of the most expensive precious metals, Rhodium.  Ruthenium is considerably less expensive than the other precious metals, and became the focus of the project. Two novel ruthenium catalysts for the conversion of morphine to hydromorphone were developed. The first was a homogeneous, water soluble ruthenium complex which, on reaction and workup, left very low residual metal contamination in the product.  To further this concept, a heterogeneous catalysts based on ruthenium black was developed.  The heterogeneous example proved to be efficient, recoverable and recyclable.

Outcome: Two catalysts were developed, one homogeneous and one heterogeneous. The heterogeneous ruthenium catalyst proved capable of efficiently converting morphine to hydromorphone and was recyclable.

Issued Patent: Ruthenium Catalysts for the Production of Hydrocodone, Hydromorphone or a Derivative Thereof  US20100261905

Project Objective: Incorporate a new impurity into an already validated HPLC method

Description:  A new impurity was found while stability testing a drug substance.  It was found that the impurity standard was not fully baseline resolved from another impurity.  The method was modified within Pharmacopeia guidelines to achieve resolution by adjusting the pH of the mobile phase.  This small change achieved the needed resolution, system suitability testing was acceptable, and a short validation of the new impurity was completed.

Outcome: The analytical method was modified to incorporate new impurity without necessitating a full re-validation of the procedure.  The method was qualified in a timely manner with minimal disruption to quality control testing lab.

Project Objective: Remove the requirement to use copper salts and chromatography in a catalyst production process

Description: The literature process to manufacture the Hoveyda-Grubbs catalyst involved using copper chloride as a phosphine sponge and chromatography to clean up the product.  A new process was designed using the ligand as solvent allowing for the removal of copper from the process. In addition a mixed solvent system was designed that resulted in the crystallization of the catalyst from the reaction mixture and recovery of crude ligand and residual ruthenium for recycle.

Outcome: A green process for manufacturing the Hoveyda-Grubbs catalyst was developed and resulted in the first significant revenue for a start-up.  The catalyst was used by customers for the production of a cyclic peptide anti-viral that targeted Hepatitis C.

Issued Patent: Chelating carbene ligand precursors and their use in the synthesis of metathesis catalysts US6620955

Project Objective:  Discover an improved delivery system for next-generation metallocene polymerization catalysts.

Discussion: Olefin polymerization catalysts are typically activated with reactive species such as methalumoxane (MAO). MAO is flammable and its composition somewhat variable. Non-coordinating anion (NCA) activators are safer to handle and more easily quantifier.  However, catalysts activated with NCAs are typically oily and insoluble in non-reactive solvents, which makes them difficult to introduce into a reactor. The activated catalyst was shown to be soluble in low molecular weight polydimethylsiloxane which was an excellent inert carrier to introduce the catalyst into gas phase reactors.

Outcome: A novel ethylene polymerization catalyst delivery system was designed that allowed for the pre-activation and injection of catalysts utilizing non-coordinating anion activators.

Issued Patent: Catalyst system method for preparing and using same in a polymerization process US6541412

Project Objective: Design a dual catalyst system that produces different polyethylene polymers in the same reactor.

Discussion:  A blended polymer is typically required to obtain the best polymer properties for polyethylene.  Manufacturing different polymers in the same reactor allows the reduction or elimination of blending.  Novel catalysts developed in-house and in conjunction with MIT demonstrated the production of highly branched, or comb polymers under the same conditions used to manufacture linear high density polyethylene. Combining the new catalyst with the novel, a pre-blended polymer was made.

Outcome:  A pre-blended polymer with excellent properties was produced by the dual catalyst system.

Issued Patent: Mixed transition metal catalyst systems for olefin polymerization US6194341

Project Objective: Reduce or remove a noxious byproduct, without significantly altering product performance of the existing chemical process

Description:  The existing process used a disulfide component that produced ethylene sulfide as a byproduct which polymerized in the reaction equipment overhead and vacuum system.  Removal of the disulfide starting material and reconfiguration of the remaining reaction components using Design of Experiments studies resulted in a far superior process and improved performance by the revised product.

Outcome: Improved process and performance of existing phosphite-based anti-wear additive for lubricants.  A tech package was delivered to the contract manufacturing plant. Scale-up of the new process from pilot to 3000L reactor proceeded with no deviations.

Issued Patent: Power transmission fluids containing alkyl phosphonates US6127323

Project Objective: Develop novel friction modifiers that allow for “fill and forget” formulations of automatic transmission fluid.  Scale process to commercial capacity.

Description: Friction modifiers available at the time were oxidatively unstable resulting in significant changed in transmission performance as fluids aged.  A new class of friction modifiers base on polyamines were designed at the bench, formulated and ultimately scaled to commercial quantity.

Outcome: Several automotive companies adopted formulations based on the new friction modifiers and phosphite that allowed for lifetime transmission fills.  Lexus in particular was an early adopter.

Issued Patent: Power transmission fluids of improved viscometric and anti-shudder properties US5942472