A common approach to tackle the poor aqueous solubility of Active Pharmaceutical Ingredients

Drug nanoparticles, commonly referred as nanocrystals, are particles made of the drug itself and have a size below 1 µm, typical a few hundreds nanometers.

A variety of oral dosage forms incorporating drug nanoparticles is marketed (e.g. fenofibrate, sirolimus, aprepitant, megestrol acetate).

Nanosizing drug particles provides enormous increases in their specific surface area and hence brings key benefits for oral formulations of poorly soluble drugs such as BCS Class II drugs.

  • improved dissolution rate
  • improved solubility
  • enhanced bioavailability
  • reduced fed/fasted variation in bioavailability
  • reduced PK variability
  • fast onset of action
  • dose reduction
  • improved dose proportionality

 

Drug nanoparticles also make it possible to overcome some problems of parenteral formulations such as toxic effects of cosolvents or surfactants which are required to dissolve poorly soluble drugs. Intravenous aqueous suspensions of drug nanoparticles have further advantage of drug targeting due to their accumulation in tumor tissues. Unique properties of drug nanoparticles have also been used to develop and market a safe long acting intramuscular depot formulation (paliperidone palmitate).

Manufacturing of drug nanoparticles

Drug nanoparticles can be produced through top-down or bottom-up processes.

Top-down processes, mainly wet ball milling and high pressure homogenization, are based on size reduction of drug particles dispersed in a aqueous vehicle and lead to the recovery of a nanosuspension. While all marketed products are produced according to these processes, the top-down approach has drawbacks which can hinder its application to some challenging APIs.

  • poor control over particle size and properties,
  • polymorphic transition and/or amorphization
  • strict crystallinity specifications for the starting APIs are required for crystallinity batch-to-batch consistency of drug nanoparticles,
  • tedious downstream processing to transform the aqueous nanosuspension into a stable solid dosage form.

 
Bottom-up processes are based on the precipitation techniques. The drug is dissolved in an organic solvent and the solution is mixed with water and stabilizers to produce a stable nanosuspension. Bottom-up processes make it possible to produce nanosuspensions with tailored size. Nevertheless, some features of these organic solvent based processes often limit their application to pharmaceutical products.

  • poor control over crystallinity
  • amorphous or metastable semi-crystalline particles are often produced
  • recovery of nanoparticles suspended in an aqueous-organic medium
  • tedious transformation into solid products starting and removal of organic solvents

StaniPharm Technology : a solvent-free bottom-up process for the manufacturing of drug nanoparticles

The StaniTab® technology is designed to extend the scope of application of nanosizing to challenging APIs which are not processable by top-down or organic solvent based bottom-up processes.

This patented unique process relies on the unique properties of supercritical fluids and consists in:

  1. dissolving the drug in supercritical carbon dioxide
  2. expanding the drug supercritical solution according to a finely controlled thermodynamic pathway in a low pressure vessel so as to produce drug nanoparticles
  3. trapping the nanoparticles onto a powder of an auxiliary substance

The StaniTab® process is thus a one-step process which leads to a dry product made of drug nanoparticles and an auxiliary substance.

The auxiliary substance is selected among common materials for the manufacturing of tablets by direct compression such as lactose, mannitol, microcrystalline cellulose.

The StaniTab® crystallisation technology makes it possible to produce nanoparticles from a variety of drug substances, provided that they are slightly soluble in supercritical CO2, and offers unique benefits:

  • tailored particle size distribution
  • fine control over crystallinity
  • possible manufacturing of stable crystalline nanoparticles starting from amorphous drugs or metastable polymorphs
  • mild operating conditions making it possible to process oxygen, heat or shear stress sensitive drugs
  • no organic solvents, no water, no stabilizers
  • easy and safe manufacturing of tablets by common mixing and direct compression operations

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