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Developing an industrial process for manufacturing hydromorphone hydrochloride through DoE and optimization

By Par Holmberg, Senior Scientist, Cambrex

Par Holmberg, Senior Scientist at Cambrex, describes a case study applying process optimization to reduce the number of synthetic

Par Holmberg, Senior Scientist at Cambrex, describes a case study applying process optimization to reduce the number of synthetic steps, eliminate hazardous reagents and allow for easier material handling of an existing, mature product, affording a new, efficient process to ensure longevity of the product in the future.

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As small molecule drugs evolve throughout their lifecycle, it is important that manufacturers look to be able to produce products efficiently and effectively to keep up with the market economics. This may lead to engineers looking to improve how processes are carried out on plant by improving the safety and handling requirements, or developing new routes using new and emerging technologies.
The opioid pain medication hydromorphone (Figure 1) was first synthesised in Germany in 1925, and introduced to the market in 1926 under the brand name Dilaudid. Traditionally, hydromorphone has been synthesised in a two-step process from morphine, however, this is inefficient and low yielding. More recently, hydromorphone has been prepared from oripavine in a two-step sequence which includes a selective hydrogenation followed by hydrolysis.

Cambrex already had in its technological portfolio a highly efficient process for making hydrocodone via a redox isomerization of concentrate of poppy straw (CPS) rich in codeine and when looking for a new synthetic route to hydromorphone, the first thought was to perform a 3-O-demethylation of hydrocodone.

3-O-demethylations of opiates can either be performed under acidic or basic conditions, however, hydromorphone is intrinsically unstable under basic conditions, so that option was ruled out.

Cambrex Figure 2.pngA survey of the relevant literature for 3-O-demethylations of opiates provided an interesting paper published in 1992, by Andre et al.1 The authors discuss the use of a methane sulfonic acid (MSA) / methionine acting as a hard acid / soft nucleophile system in the 3-O-demethylation of different opiates, a method originally reported by Yajima2 and Kiso3 in the deprotection of peptides. The paper reported how naloxone, which is structurally similar to hydromorphone, can be made from N-allyl noroxycodone. Naloxone exerts an antagonistic effect on the opioid receptor and has recently received wide attention from the media in its use of treating opioid overdoses.

Andre et al treated N-allyl-noroxycodone with 30 equivalents of MSA and 1.5 equivalents of methionine (Figure 2) for 15 hours at 40°C, affording naloxone in 60% yield after recrystallization.

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When Cambrex attempted to replicate the conditions using hydrocodone as the starting material (Figure 3) the result was disappointing. The reaction yielded a black, sticky, tar-like product, however, ultra-performance liquid-chromatography with mass spectrometry (UPLC-MS) showed the presence of hydromorphone in the mixture.

It became clear that the appropriate choice of the hard acid and soft nucleophile was essential for the success of developing a manufacturing process for hydromorphone. What followed was a development process involving screening various combinations of acid, co-acid and sulfide. The use of a DynaBloc heater, combined with Design of Experiment (DoE) software afforded the generation the qualitative/quantitative results within a short time frame. The DynaBloc heater allows 18 reactions to be run in parallel, and DoE is a systematic method to determine the relationship between factors affecting a process and the output of that process. The DoE software enabled reaction model prediction by statistical analysis, allowing the team to better assess where to direct their process development. In all, over 450 reactions were run using a combination of 6 acids, 11 co-acids and 40 different sulfides.

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The use of UPLC-MS in the project facilitated the analysis of a large set of reaction mixtures within a short period of time providing not only chromatography data but also mass data. These studies identified trichloroacetic acid (TCA) as the solvent, a mixture of MSA / trifluoromethanesulfonic acid (triflic acid, TfOH) as the hard acid and dibutyl sulfide as the soft nucleophile, as the optimal system to execute the 3-O-demethylation of hydrocodone.
This groundwork laid the foundation for the first generation industrial process for the manufacturing of hydromorphone, shown in Figure 4. This is essentially a two-step process (one of which is telescoped without isolation of the intermediate) from hydrocodone to the hydrochloride salt of hydromorphone, followed by a recrystallisation in methyl ethyl ketone (MEK).
This process was successful in that it demonstrated that codeine CPS could be converted to hydromorphone without the need for isolation of the intermediate hydrocodone. Surprisingly, hydromorphone was not isolated as the expected MSA salt, but as the triflate salt (identified by 19F nuclear magnetic resonance spectroscopy). The isolation of the crude triflate salt was not trivial as the product had a tendency to oil out in the presence of different anti-solvents, however, MEK was found to precipitate out the triflate salt. A seeding protocol was implemented in the production to ensure robustness of the process.
The hydromorphone triflate could directly be converted to the corresponding hydrochloride salt, thus avoiding any of the instability issues of hydromorphone under basic conditions.  
There were drawbacks with the first generation process, one of which was the use of triflic acid which is one of the strongest acids known and reacts with glass and stainless steel. This limited the type of vessels that could be used for process at large scale. Special precautions needed to be taken in the plant to ensure the safety of the operators when handling triflic acid, and the use of trichloracetic acid in the process which is hygroscopic also led to handling issues.

From this success, further development work was carried out to overcome some of the issues associated from the route. The objectives of this second generation process were to:
  • Remove the use of triflic acid to eliminate materials of construction and safety issues
  • Switch the hygroscopic solid trichloracetic acid to trifluoroacetic acid (TFA) to improve handling
  • Remove one step in the process by eliminating the salt swap i.e. isolating hydromorphone hydrochloride directly from the reaction mixture.
The successful second generation process (Figure 5) fulfilled all the goals, and afforded the hydrochloride salt of hydromorphone in a 74% yield. Hydrocodone was treated with TFA, dibutylsulfide and MSA with a catalytic amount of water. The role of water had been shown by DOE studies to play a critical role for the outcome of the reaction when using TFA instead of TCA. The reaction was run for at least 16 hr at 50 ± 5°C, before determining reaction completion by using UPLC-MS.
The intermediate hydromorphone was not isolated, but hydrochloric acid was charged to the mixture, followed by the addition of an anti-solvent to provide a thick slurry. The hydromorphone hydrochloride was conveniently isolated by a filtration as a white to off-white solid.

The work carried out was successful in that two highly selective hydrocodone O-demethylation processes have been developed for the synthesis of hydromorphone hydrochloride. Both processes gave the desired product in good yield and high purity.
Process optimisation led to a more efficient second generation process that reduced the number of synthetic steps, eliminated hazardous reagents and allowed for easier material handling.
1. Andre J-D et al. Synthetic Communications 1992;22:2313-27.
2. Yajima H et al. J Chem Soc Commun 1974;21:107-108.
3. Kiso Y et al. Protein Research Foundation, Osaka, 25 (1979).