Critical material attributes (CMAs) of strip films loaded with poorly water-soluble drug nanoparticles: I. Impact of plasticizer on film properties and dissolution

Abstract

Recent studies have demonstrated polymer films to be a promising platform for delivery of poorly water-soluble drug particles. However, the impact of critical material attributes, for example plasticizer, on the properties of and drug release from such films has yet to be investigated. In response, this study focuses on the impact of plasticizer and plasticizer concentration on properties and dissolution rate of polymer films loaded with poorly water-soluble drug nanoparticles. Glycerin, triacetin, and polyethylene glycol were selected as film plasticizers. Griseofulvin was used as a model Biopharmaceutics Classification System class II drug and hydroxypropyl methylcellulose was used as a film-forming polymer. Griseofulvin nanoparticles were prepared via wet stirred media milling in aqueous suspension. A depression in film glass transition temperature was observed with increasing plasticizer concentration, along with a decrease in film tensile strength and an increase in film elongation, as is typical of plasticizers. However, the type and amount of plasticizer necessary to produce strong yet flexible films had no significant impact on the dissolution rate of the films, suggesting that film mechanical properties can be effectively manipulated with minimal impact on drug release. Griseofulvin nanoparticles were successfully recovered upon redispersion in water regardless of plasticizer or content, even after up to 6 months’ storage at 40 °C and 75% relative humidity, which contributed to similar consistency in dissolution rate after 6 months’ storage for all films. Good content uniformity (<4% R.S.D. for very small film sample size) was also maintained across all film formulations.

Critical material attributes (CMAs) of strip films loaded with poorly water-soluble drug nanoparticles: III. Impact of drug nanoparticle loading

“…Steiner et al (2016) also observed brittleness in poorly water-soluble drug nanoparticle-loaded films with similarly high drug loading using a lower molecular weight grade of HPMC as film-forming polymer. Although it may be possible to push the maximum drug particle loading in films above 45–50 wt% while maintaining acceptable film mechanical properties with more thorough formulation development, such as modulation of plasticizer content (Krull et al, 2016b), these results suggest that film brittleness is a major hurdle to overcome to achieve higher drug particle loadings in strip films for practical use.…”

“…Various particle engineering techniques have also been employed to improve poorly water-soluble drug dissolution rate for incorporation into strip films. These include wet stirred media milling (WSMM) (Davé et al, 2014; Krull et al, 2017; Krull et al, 2016a; Krull et al, 2016b; Krull et al, 2015; Sievens-Figueroa et al, 2012a; Susarla et al, 2015; Susarla et al, 2013) and high pressure homogenization (Lai et al, 2015; Shen et al, 2013) to reduce drug particle size, as well as liquid antisolvent precipitation (Beck et al, 2013) and melt emulsification (Bhakay et al, 2016) to produce drug nanoparticles via bottom-up approach. However, one perceived limitation shared by all means of incorporating poorly water-soluble drug into films is the existence of an inherent limitation on drug loading (Borges et al, 2015b; Dixit and Puthli, 2009; Hoffmann et al, 2011).…”

“…The majority of work in this area has either focused on establishing a means of particle engineering that is suitable for incorporation into the film platform (Beck et al, 2013; Bhakay et al, 2016; Krull et al, 2015; Prodduturi et al, 2005; Sievens-Figueroa et al, 2012a; Visser et al, 2015) or the impact of critical material attributes (CMAs) on their performance (Krull et al, 2016a; Krull et al, 2016b; Susarla et al, 2015). In most cases, drug loading in films was kept below 20 wt% with none above 30 wt%, presumably to avoid potential confounding influences of high drug loading on other experimental factors under investigation.…”

Bioavailability Enhancement of Poorly Water-Soluble Drugs via Nanocomposites: Formulation–Processing Aspects and Challenges

“…In fact, drying is generally perceived as a stabilization step for nanocrystals to avoid typical deterioration occurring in a liquid nanosuspension, such as Ostwald ripening, particle aggregation, sedimentation, and creaming [ 56 , 57 ]. For all the aforementioned reasons, drug nanosuspensions have been dried, as illustrated in Figure 1 , via spray drying [ 33 , 34 , 58 , 59 , 60 , 61 , 62 ], fluid bed coating/granulation/drying [ 8 , 60 , 63 , 64 , 65 , 66 ], spray-freeze drying [ 7 , 67 ], freeze drying [ 68 , 69 , 70 , 71 , 72 ], vacuum drying [ 73 , 74 ], nanoextrusion [ 75 , 76 , 77 , 78 ], and wet casting–drying [ 40 , 79 , 80 , 81 , 82 , 83 ]. Drying processes convert drug nanosuspensions into nanocomposites that encapsulate or carry drug nanoparticles and their clusters dispersed as a secondary phase in the matrix of dispersants (stabilizers used in nanosuspensions and other excipients).…”

Fabrication of multicomponent amorphous bufadienolides nanosuspension with wet milling improves dissolution and stability

“…A plasticizer or intermolecular association would result in a higher free volume than that expected from ideal mixing, leading to higher molecular mobility and a lower T g value [26]. The impact of SLS on the T g of the bufadienolide nanosuspension with constant CCS can be seen in Figure 6(c-e), where decreasing concentrations of SLS led to a clear increase in T g , a trend that has been observed for multiple polymer-surfactant combinations [27,28]. These findings indicate that bufadienolides can be incorporated into a…”