427913 Amorphous Solid Dispersion of Poorly Soluble API By Hot Melt Extrusion (HME) and Spray Drying (SD): A Rational Screening Approach

Wednesday, November 11, 2015: 9:45 AM
Ballroom D (Salt Palace Convention Center)
Amrit Paudel1, Annalisa Mercuri2, Stefan Mohr2, Massimo Bresciani3 and Johannes G. Khinast4, (1)Advanced Products and Delivery, RCPE, Graz, Austria, (2)RCPE, Graz, Austria, (3)Research Center Pharmaceutical Engineering GmbH, Graz, Austria, (4)Research Center Pharmaceutical Engineering (RCPE), Graz, Austria

Amorphous solid dispersion of poorly soluble API by hot melt extrusion (HME) and spray drying (SD): A rational screening approach

A.Paudel1, A. Mercuri1, S. Mohr1, M. Bresciani1, J.G. Khinast1

1Research Center Pharmaceutical Engineering, Graz, Austria

Polymeric amorphous solid dispersion (ASD) of poorly water soluble active pharmaceutical ingredients (APIs) are one of the promising strategies of solubility and dissolution rate enhancement, and hence, tackling the growing challenges in oral bioavailability (1). Hot melt extrusion (HME) and spray drying (SD) are two industrial technologies for manufacturing ASD (2). Major hurdle associated to the ASD is the possible risk of crystallization of amorphous form during storage and/or administration, thus negating the claimed solubility advantage. Since solid-state API-carrier molecular miscibility and carrier-induced supersaturation play a critical role towards stabilization of ASD and in vivo performance, selection of suitable carrier (s), optimal drug loading and appropriate manufacturing process/parameters is crucial for the success of this formulation strategy (3). HME and SD both exhibit different pros and cons associated with processability of the range of carriers, available solvent range, thermal degradation and molecular, particulate and bulk-level properties of resulting amorphous intermediates. Thus, there is a different degree of downstream processability for finished dosage development.

This work aims towards a multi-methodological approach, using a model drug candidate and a wide diversity of ASD carriers, such as Soluplus, HPMC, HPMC-AS, PVPVA 64 and their blends with Eudragit E or HPC: (i) solution-state excipient-induced biorelevant supersaturation, (ii) film-based mini-formulation preparation via solution casting (SC) and melt-quench-cooling (MC) using selected carriers, (iii) solid-state characterization and mini-dissolution studies, (iv) formulating ASD formulation via HME and SD and (v) solid-state characterization, in vitro biorelevant dynamic dissolution and accelerated short-term physical stability of formulations prepared by HME and SD.

The first set of carriers was selected based on the extent of API supersaturation generation and its maintenance in fasted-state simulated intestinal fluid (FaSSIF). These were Soluplus, HPMC and HPMC-AS/HPC blends. SC and MC films were prepared of API with the varying ratios of latter polymers using HME relevant temperatures and SD relevant solvents, respectively. Drug-carrier miscibility and interaction, glass transition, crystallinity and wettability of film formulations were evaluated using several methods, such as DSC, pXRD, ATR-FTIR spectroscopy, contact angle etc. Based on the outcome, supersaturating formulations with a homogenous amorphous phase were generated by HME and/or SD using different carriers (Soluplus, HPMC and HPMC-AS/HPC). Solid-state characterization, in vitro biorelevant dynamic dissolution and accelerated short term stability study were performed on formulations prepared by HME and SD.

It was found that supersaturation screening and small-scale dissolution tests can partially predict the in vitro behaviour of ASDs. Film based screening (SC vs MC) aids in predicting the performance rank order of ASD formulations. The results showed that strong functional interactions like API-carrier H-bonding is not always a prerequisite for stabilizing miscible API-polymer systems. Comparable in vitro dissolution behaviour of amorphous and partially crystalline Soluplus based dispersion implied that complete amorphicity of API in dispersion is not essential for enhancing in vitro performance of solid dispersion. ASD derived from HME and SD can behave completely different when exposed to elevated T/%RH, even though identical carrier with identical composition and physical states are used.


1.      Van den Mooter, G. (2012) The use of amorphous solid dispersions: A formulation strategy to overcome poor solubility and dissolution rate. Drug Discovery Today: Technologies 9, e79–e85.

2.      Paudel, A., Worku, Z.A., Meeus, J., Guns, S., Van den Mooter, G. (2013) Manufacturing of solid dispersions of poorly water soluble drugs by spray drying: formulation and process considerations, International journal of pharmaceutics 453, 253-284.

3.      Paudel, A., Van Humbeeck, J., Van den Mooter, G. (2010) Theoretical and experimental investigation on the solid solubility and miscibility of naproxen in poly (vinylpyrrolidone), Molecular pharmaceutics 7, 1133-1148.

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