Ralph Diodone

Improved Human Bioavailability of Vemurafenib, a Practically Insoluble Drug, Using an Amorphous Polymer-Stabilized Solid Dispersion Prepared by a Solvent-Controlled Coprecipitation Process

The present work deals with improving the solubility of vemurafenib, a practically insoluble drug, by converting it into an amorphous-solid dispersion using a solvent-controlled precipitation process. The dispersion containing vemurafenib and hypromellose acetate succinate (HPMCAS), an enteric polymer, is termed microprecipitated bulk powder (MBP), in which the drug is uniformly dispersed within the polymeric substrate. HPMCAS was found to be the most suitable polymer for vemurafenib MBP, among a series of enteric polymers based on superior physical stability and drug-release characteristics of the MBP. The MBP provided a greater rate and extent of dissolution than crystalline drug, reaching an apparent drug concentration of 28-35 µg/mL, almost 30-fold higher than solubility of crystalline drug at 1 µg/mL. The supersaturation was also maintained for more than 4 h. Upon exposure to high temperature and humidity, the MBP was destabilized, resulting in crystallization and lower dissolution rate. The control of moisture and temperature is essential to maintain the stability of the MBP. In a relative human bioavailability study, vemurafenib MBP provided a four- to fivefold increase in exposure compared with crystalline drug. Improving solubility with an amorphous-solid dispersion is a viable strategy for the development of practically insoluble compounds.

MBP Technology: Process Development and Scale-Up

Microprecipitated bulk powder (MBP) is an innovative approach to stabilize the amorphous state of the active pharmaceutical ingredient (API) in a coprecipitate with (ionic) polymers to increase the bioavailability of poorly soluble drugs. This chapter focuses on process development, scale-up, and its challenges for manufacturing of MBP on commercial scale. A preliminary formulation is established based on the physicochemical properties of API, small-scale screening, and formulation trials to help select the polymer, optimal drug loading, and initial process. It is well recognized that for amorphous solid dispersion (ASD), drug loading competes directly with the stability of the amorphous product especially the physical stability. These stability challenges can manifest either during manufacturing of the amorphous dispersion, downstream processing, or during storage. Use of structured development approach helps to mitigate some risks associated with the MBP development, but the successful scale-up of process remains one of the most formidable challenges. From a simplistic approach, the MBP process can be considered as a solvent–antisolvent precipitation with rapid precipitation rate to capture the amorphous form of drug. To maintain the comparability of product between different scales and phases of development, it is mandatory to achieve similar precipitation rates. Fundamental aspects of MBP technology and process are described in the previous chapter and the key process parameters considered necessary for process development are presented in this work.

Efficient Industrial Synthesis of the MDM2 Antagonist Idasanutlin via a Cu(I)-catalyzed [3+2] Asymmetric Cycloaddition

A concise asymmetric synthesis has been developed to prepare idasanutlin, a small molecule MDM2 antagonist. Idasanutlin is currently being investigated as a potential treatment for various solid tumors and hematologic malignancies. The highly congested pyrrolidine core, containing four contiguous stereocenters, was constructed via a Cu(I)/(R)-BINAP catalyzed [3+2]-cycloaddition reaction. This optimized copper(I)-catalyzed process has been used to produce more than 1500 kg of idasanutlin. The manufacturing process will be described, highlighting the exceptionally selective and consistent cycloaddition/isomerization/hydrolysis sequence. The excellent yields, short cycle times and reduction in waste streams result in a sustainable production process with low environmental impact.