The design and development of high drug loading amorphous solid dispersion for hot-melt extrusion platform

Abstract

Amorphous solid dispersion (ASD) is a formulation strategy extensively used to enhance the bioavailability of poorly water soluble drugs. Despite this, they are limited by various factors such as limited drug loading, poor stability, drugexcipient miscibility and the choice of process platforms. In this work, we have developed a strategy for the manufacture of high drug loaded ASD (HDASD) using hot-melt extrusion (HME) based platform. Three drug-polymer combinations, indomethacin-Eudragit®E, naproxen-Eudragit®E and ibuprofen-Eudragit®E, were used as the model systems. The design spaces were predicted through Flory-Huggins based theory, and the selected HDASDs at pre-defined conditions were manufactured using HME and quench-cooled melt methods. These HDASD systems were also extensively characterised via small angle/wide angle x-ray scattering, differential scanning calorimetry, Infrared and Raman spectroscopy and atomic force microscopy. It was verified that HDASDs were successfully produced via HME platform at the pre-defined conditions, with maximum drug loadings of 0.65, 0.70 and 0.60 w/w for drug indomethacin, ibuprofen and naproxen respectively. Enhanced physical stability was further confirmed by high humidity (95%RH) storage stability studies. Through this work, we have demonstrated that by the implementation of predictive thermodynamic modelling, HDASD formulation design can be integrated into the HME process design to ensure the desired quality of the final dosage form.

Drug-Rich Phases Induced by Amorphous Solid Dispersion: Arbitrary or Intentional Goal in Oral Drug Delivery?

“…In the ASD system, different amorphous polymeric or small molecular excipients are utilized to stabilize the amorphous drug during the storage as well as to enhance the solubility and dissolution rate of the drug in solution [21][22][23][24]. While amorphous drug molecules are considered to be homogeneously dispersed within the excipients in an ideal ASD system, an amorphous-amorphous phase separation (AAPS) phenomenon is often observed during the manufacturing or storage due to the imperfect miscibility of drug and excipients [29,[75][76][77]. The AAPS phenomenon can be normally interpreted by the schematic phase diagram of ASD illustrated in Figure 2A, where the solid blue line indicates the binodal line.…”

“…The ASD products approved by FDA in the last 5 years are briefly summarized in Table 1, indicating an ascending phase of this technology for wide adoptions in the pharmaceutical industry [20,24,25]. This summary is adapted from several references [26][27][28][29]. Details of the approval year, active ingredients, companies and dosage forms are derived from the FDA drug database and annual approval reports [17].…”

Molecular Interactions in Solid Dispersions of Poorly Water-Soluble Drugs

“…Weak physical bonds (formed by non-covalent interactions) such as hydrogen bonds, ionic bonds, van der Waals, dipole-dipole interactions and acid-base interactions are common interactions occurred between components in SDs [ 26 , 34 , 35 , 36 , 37 , 38 ]. Among them, hydrogen bonding formation is typically observed in SDs [ 39 , 40 , 41 , 42 ]. The formation of these bonds between a drug and one of the SD components may prevent self-association between drug molecules, leading to changes in the crystallization kinetics [ 43 ].…”

Direct Powder Extrusion 3D Printing of Praziquantel to Overcome Neglected Disease Formulation Challenges in Paediatric Populations

“…Various approaches have been evaluated to overcome the aforementioned obstacles, one being the transformation of the drug solid state structure from crystalline to amorphous [ 15 , 16 , 17 , 18 ]. The use of an amorphous form of the drug requires its physical stabilisation in the formulation, which can be achieved by the formation of amorphous solid dispersions (ASDs).…”