Increasing global access to the high-volume HIV drug nevirapine through process intensification

Verghese, Jenson; Kong, Caleb J.; Rivalti, Daniel; Yu, Eric; Krack, Rudy; Alcázar, Jesús; Manley, Julie B.; McQuade, D. Tyler; Ahmad, Saeed; Belecki, Katherine; Gupton, B. Frank

doi:10.1039/c7gc00937b

Cited by 32 publications

(47 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[1] An umber of innovative medicines has made HIV am anageable disease;h owever,t he cost of treatment is still prohibitive for many patients in lower income countries. [4] We became interested in Dolutegravir due to its importance in HIV combination therapy. The initiative has led to an umber of reported studies.…”

mentioning

confidence: 99%

See 1 more Smart Citation

7‐Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir

et al. 2018

Self Cite

View full text Add to dashboard Cite

Dolutegravir (DTG), an important active pharmaceutical ingredient (API) used in combination therapyf or the treatment of HIV,has been synthesized in continuous flow. By adapting the reported GlaxoSmithKline process chemistry batch route for Cabotegravir,D TG was produced in 4.5 hi n sequential flowoperations from commercially available materials.Key features of the synthesis include rapid manufacturing time for pyridone formation, one-step direct amidation of afunctionalized pyridone,and telescoping of multiple steps to avoid isolation of intermediates and enable for greater throughput.

show abstract

mentioning

confidence: 99%

“…The initiative has led to an umber of reported studies. [4] We became interested in Dolutegravir due to its importance in HIV combination therapy. Dolutegravir (DTG) 1 (Figure 1) is an HIV integrase inhibitor co-developed by GlaxoSmithKline (GSK) and Shinogi that was approved by the Food and Drug Administration (FDA) in 2013.…”

mentioning

confidence: 99%

7‐Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…39 The recent demonstration of the continuous flow synthesis of nevirapine uses advanced starting materials, 2-chloro-3-amino-4-picoline (CAPIC) and MeCAN (2-(cyclopropylamino)nicotinate). 10 The syntheses of CAPIC and MeCAN are summarised below ( Fig. 2).…”

Section: Api and Starting Materials Synthetic Routesmentioning

confidence: 99%

“…Figure 3: Nevirapine continuous synthetic strategy from CAPIC and MeCAN. 10 Fig. 4 shows the process flowsheet for nevirapine CPM based on the published continuous flow synthesis.…”

Section: Api and Starting Materials Synthetic Routesmentioning

confidence: 99%

“…5,32 This work conducts a systematic comparative evaluation of CPM process alternatives for nevirapine based upon the published synthetic routes via steady-state process modelling and optimisation. [10][11][12] The continuous process for nevirapine demonstrated in the literature are first presented. A conceptual continuous crystallisation process is considered for comparison to the demonstrated batch crystallisation process.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Process Design and Optimization for the Continuous Manufacturing of Nevirapine, an Active Pharmaceutical Ingredient for HIV Treatment

Diab

McQuade

Gupton

et al. 2019

Org. Process Res. Dev.

Self Cite

View full text Add to dashboard Cite

Development of efficient and cost-effective manufacturing routes towards HIV active pharmaceutical ingredients (APIs) is essential to ensure their global, affordable access. Continuous pharmaceutical manufacturing (CPM) is a new production paradigm for the pharmaceutical industry, whose potential for enhanced efficiency and economic viability over currently implemented batch protocols offers promise for improving HIV API production. Nevirapine is a widely-prescribed HIV API, whose continuous flow synthesis was recently demonstrated. This paper presents technoeconomic optimisation of nevirapine CPM, including the continuous flow synthesis and a conceptual continuous crystallisation. Arrhenius law parameter estimation from published reaction kinetic data allows explicit modelling of the temperature-dependence of reaction performance and an experimentally validated aqueous API solubility computation method is used to model crystallisation processes. A nonlinear optimisation problem for cost minimisation is formulated for comparative evaluation of different plant designs. Higher reactor temperatures are favoured for CPM total cost minimisation, while lower pH (less neutralising agent) is required to attain the desired plant capacities for cost optimal configurations compared to batch crystallisation designs. Suitable E-factors for pharmaceutical manufacturing are attained when higher solvent recoveries are assumed. Implementing CPM designs significantly lowers the nevirapine cost of goods towards reducing the price of societally-important HIV medicines.

show abstract