Innovations in Pharma Science - Pharmaceutical Technology

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PharmTech Europe

Innovations in Pharma Science
Pharmaceutical Technology is pleased to recognize the winners of its Innovations in Pharma Science Awards.

Pharmaceutical Technology
Volume 32, Issue 12, pp. 46-47

Solid complexes with ionic polymers

Created by Navnit Shah, Harpreet Sandhu, Wantanee Phuapradit, Raman Iyer, Anthony Albano, D. Desai, Duk Choi, Kin Tang, Hung Tian, Hitesh Chokshi, Zenaida Go, Waseem Malick, Roumen Radinov, Ashish Shankar, Steven Wolff, and Hans Mair

Hoffmann-LaRoche (Nutley, NJ)

Poor solubility and bioavailability present significant hurdles for the optimal oral delivery of compounds. Roche scientists were faced with one such compound having excellent in vitro potency but very low oral bioavailability. A team of Roche scientists discovered novel approaches to converting a crystalline drug into its amorphous form and simultaneously embedding it in an ionic polymer to immobilize the amorphous molecules and prevent nucleation, thus stabilizing the amorphous form. The selection of an ionic polymer along with an innovative process created a stable amorphous form that provided desirable pharmacokinetic profile of the drug. The pharmacokinetic profile produced not only the desired efficacy but also improved the safety margin by reducing side effects. Overall, the drug is precipitated in an ionic polymer in an amorphous form (microprecipitated bulk powder, MBP) at the nano-size or molecular level, thus enhancing its bioavailability (10- to 20-fold higher compared with micronized form of the drug). The stabilization of the amorphous form is imparted by the ionic nature of the polymer due to its high molecular weight and high-glass transition temperature. This technology was scaled-up and is being used for Phase I– II clinical studies of several Biopharmaceutical Classification System Class 2 (low solubility and high permeability) and Class 4 (low solubility and low permeability) compounds (see manufacturing process above). Several technology patents have been issued, and some are pending.


Raltegravir API process design

Created by Guy Humphrey and Ross Miller

Process Research, Merck Research Laboratories (Rahway, NJ)

Approved in the United States in October 2007, "Isentress" (raltegravir) is a first-in-class HIV integrase inhibitor for the treatment of HIV/AIDS. While the first-generation process for making the active pharmaceutical ingredient (API) provided a reliable method to support the launch of raltegravir, a more productive and greener process was required for long-term manufacturing purposes. Merck chemists redesigned the original process, culminating in a vastly more efficient process. Key features include a highly innovative N-methylation step in which an initial mixture of N- and O-methylated products are funneled to the desired product; a 1.6-fold increase in overall yield (83% versus 52%); and a >3-fold increase in productivity, resulting in reduced waste byproducts of 253 kg per kg of API of raltegravir, as well as elimination of hazardous methyl iodide. This process recently has been implemented at manufacturing scale.


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