Development Considerations for Nanocrystal Drug Products

Abstract

Nanocrystal technology has emerged as a valuable tool for facilitating the delivery of poorly water-soluble active pharmaceutical ingredients (APIs) and enhancing API bioavailability. To date, the US Food and Drug Administration (FDA) has received over 80 applications for drug products containing nanocrystals. These products can be delivered by different routes of administration and are used in a variety of therapeutic areas. To aid in identifying key developmental considerations for these products, a retrospective analysis was performed on the submissions received by the FDA to date. Over 60% of the submissions were for the oral route of administration. Based on the Biopharmaceutics Classification System (BCS), most nanocrystal drugs submitted to the FDA are class II compounds that possess low aqueous solubility and high intestinal permeability. Impact of food on drug bioavailability was reduced for most nanocrystal formulations as compared with their micronized counterparts. For all routes of administration, dose proportionality was observed for some, but not all, nanocrystal products. Particular emphasis in the development of nanocrystal products was placed on the in-process tests and controls at critical manufacturing steps (such as milling process), mitigation and control of process-related impurities, and the stability of APIs or polymorphic form (s) during manufacturing and upon storage. This emphasis resulted in identifying challenges to the development of these products including accurate determination of particle size (distribution) of drug substance and/or nanocrystal colloidal dispersion, identification of polymorphic form (s), and establishment of drug substance/product specifications.

Nanocrystals of Poorly Soluble Drugs: Drug Bioavailability and Physicochemical Stability

“…Following this pioneering study, many others confirmed the effectiveness of nanocrystals in improving drug bioavailability after oral administration, leading to a significant number of drug products in clinical trials or already on the market. To understand the importance of nanocrystals in the pharmaceutical field, one may note that until May 2017, the United States (US) Food and Drug Administration (FDA) has received over 80 applications for drug products containing nanocrystals, and over 60% of the submissions were for the oral route of administration [ 108 ].…”

“…This review shows that most of the drug products are intended for an oral administration and that the pharmaceutical dosage forms are mainly tablets, capsules, or oral suspensions. In addition, one could note that the preferred technology applied is the media milling, a top-down technology that is probably better managed by the pharmaceutical industry, and that must accurately control all of the critical production factors through in-process tests and quality control end tests [ 108 ].…”

Raman Spectroscopy for Quantitative Analysis in the Pharmaceutical Industry

“…In addition, it presents greater bioadhesiveness to the biological membranes compared to the drug in the micrometric scale. Such advantages potentially improve the safety and efficacy of the drugs, allowing dose reduction (89)(90)(91)(92).…”

“…In recent decades, there has been a significant rise in the development of drug nanocrystals. As of 2017, more than 80 drug nanocrystal applications were submitted to the FDA (90). The critical attribute characteristics of drug nanocrystals such as size, particle-size distribution and mean particle diameter, along with morphological analyses are fundamental to evaluate crystalline forms and to optimize size-dependent properties (90,93,94).…”

Promising nanotherapy in treating leishmaniasis

“…As a result, drug absorption can be increased independent of the fed or fasting state (Müller et al, 2011). However, it is important to ensure the physical chemical properties of the drug nanocrystal during the manufacturing process and in storage throughout its shelf life (Chen et al, 2017) since these characteristics are critical for drug dissolution velocity in the nanosuspension. Kayser et al (2003) develop a nanosuspension of AMB by highpressure homogenization, using polysorbate 80 and poloxamer P188.…”