3 research outputs found
A Model-Based Methodology for Spray-Drying Process Development
Solid amorphous dispersions are frequently used to improve the solubility and, thus, the bioavailability of poorly soluble active pharmaceutical ingredients (APIs). Spray-drying, a well-characterized pharmaceutical unit operation, is ideally suited to producing solid amorphous dispersions due to its rapid drying kinetics. This paper describes a novel flowchart methodology based on fundamental engineering models and state-of-the-art process characterization techniques that ensure that spray-drying process development and scale-up are efficient and require minimal time and API. This methodology offers substantive advantages over traditional process-development methods, which are often empirical and require large quantities of API and long development times. This approach is also in alignment with the current guidance on Pharmaceutical Development Q8(R1). The methodology is used from early formulation-screening activities (involving milligrams of API) through process development and scale-up for early clinical supplies (involving kilograms of API) to commercial manufacturing (involving metric tons of API). It has been used to progress numerous spray-dried dispersion formulations, increasing bioavailability of formulations at preclinical through commercial scales
Millisecond Self-Assembly of Stable Nanodispersed Drug Formulations
We report the development of a new
spray-drying and nanoparticle assembly process (SNAP) that enables
the formation of stable, yet rapidly dissolving, sub-200 nm nanocrystalline
particles within a high <i>T</i><sub>g</sub> glassy matrix.
SNAP expands the class of drugs that spray-dried dispersion (SDD)
processing can address to encompass highly crystalline, but modestly
hydrophobic, drugs that are difficult to process by conventional SDD.
The process integrates rapid precipitation and spray-drying within
a custom designed nozzle to produce high supersaturations and precipitation
of the drug and high <i>T</i><sub>g</sub> glassy polymer.
Keeping the time between precipitation and drying to tens of milliseconds
allows for kinetic trapping of drug nanocrystals in the polymer matrix.
Powder X-ray diffraction, solid state 2D NMR, and SEM imaging shows
that adding an amphiphilic block copolymer (BCP) to the solvent gives
essentially complete crystallization of the active pharmaceutical
ingredient (API) with sub-200 nm domains. In contrast, the absence
of the block copolymer results in the API being partially dispersed
in the matrix as an amorphous phase, which can be sensitive to changes
in bioavailability over time. Quantification of the API–excipient
interactions by 2D <sup>13</sup>C–<sup>1</sup>H NMR correlation
spectroscopy shows that the mechanism of enhanced nanocrystal formation
is not due to interactions between the drug and the BCP, but rather
the BCP masks interactions between the drug and hydrophobic regions
of the matrix polymers. BCP-facilitated SNAP samples show improved
stability during aging studies and rapid dissolution and release of
API <i>in vitro</i>