Crystallisation of amorphous fenofibrate and potential of the polymer blend electrospun matrices to stabilise in its amorphous form

Fenofibrate was chosen as the drug of interest in this study because of its poor water-solubility, highly unstable amorphous state and unpredictable crystallisation behaviour. The crystallisation behaviour of amorphous fenofibrate is essential information that primarily corresponds to the physical stability of solid dispersion formulations. This project aims to probe how to control the crystallisation of amorphous fenofibrate, enhance its aqueous solubility and improve its physical stability by using electrospun polymer blend matrices. A range of characterisation technologies including MTDSC, ATR-FTIR, PXRD, SCXRD, SEM, TEM, HS-PLM, nano-TA and ss-NMR were used to characterise the physicochemical properties of both the crystallisation process of fenofibrate, and fenofibrate solid dispersions. The amorphous fenofibrate was crystallised using heterogeneous nucleation techniques, including surface disruption and impurity addition (talc). The presence or absence of an open top surface (OTS) was found to be one of the key factors which dictated the crystallisation of the amorphous fenofibrate into specific polymorphs. The use of thermal treatment in addition to OTS was able to finely tune the selectivity of the crystallisation of fenofibrate to form I or/and form IIa. The use of a low percentage of talc as heterogeneous nuclei resulted in the crystallisation of the new fenofibrate polymorph III. The polymer blend fibres prepared by electrospinning were phase separated solid dispersions that improved the aqueous solubility of the fenofibrate in comparison to the fenofibrate crystals. The drug-polymer and polymer-polymer miscibility were found to be the key parameters that affected the physical stability of the incorporated amorphous drug and the phase separation in the formulations. Additionally, the in situ phase separation of the hydrophilic and hydrophobic polymers in the blends led to modified drug release. The drug release rate could be fine-tuned by altering the ratio of the polymers. The new knowledge generated by this work relates to the following areas: 1) an improved understanding of the crystallization process of fenofibrate and its polymorphic control; 2) the use of polymer blend matrices in electrospun fibres that leads to the stabilization of amorphous drugs when they are incorporated in those fibres; and 3) the modification of the drug release profiles via the use of hydrophilic and hydrophobic polymer blend matrices for electrospinning

Isoflavone content and antioxidant activity of Thai fermented soybean and its capsule formulation

Soybeans (Glycine max) are usually eaten as processed foods. Fermented soybeans are among the most popular of these processed foods. The aim of this study was to determine the effect of fermentation duration on isoflavone content and antioxidant activity of fermented soybeans. Capsule formulation of fermented soybeans was also studied. The Thai soybean variety, Rajamangala60, was fermented with Aspergillus oryzae. Isoflavone content and antioxidant activity were studied at 0, 12, 18,36, 48, 96, 120, 168, 240, 360 and 480 h of fermentation duration. The results showed that isoflavone glycones (daidzin and genistin) decreased during fermentation, but aglycones (daidzein and genistein) increased. The highest amount of isoflavone aglycones was 384.30 ± 4.60 and 116.50 ± 1.56 mg/100 g fermented soybeans for daidzein and genistein, respectively. Antioxidant activity of fermented soybeans was evaluated by ABTS cation radical scavenging and ferric reducing antioxidant power(FRAP) methods. Antioxidant activity of fermented soybeans is increased during fermentation. Increases in isoflavone aglycones content and antioxidant activity were related to fermentation duration. The highest antioxidant activity of fermented soybean was found at the 240 h of fermentation with trolox equivalent antioxidant capacity (TEAC) 1.98 ± 0.09 ìg trolox/g fermented soybean and FRAP value of 0.623 ± 0.002 g FeSO4/g fermented soybean. Soybeans fermented for 240 h were thenformulated as capsules by a wet granulation method. They were then assessed for appearance, weight variation, disintegration time and antioxidative properties. The results showed that fermented soybeancapsules conformed to USP32/NF27 criteria on weight variation and disintegration. Their antioxidant activity was lower than 240 h fermented soybeans, but still higher than the non-fermented ones (p <0.05)

The use of polymer blends to improve stability and performance of electrospun solid dispersions: The role of miscibility and phase separation

© 2021 Elsevier B.V. All rights reserved. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1016/j.ijpharm.2021.120637Solid dispersion-based nanofiber formulations of poorly soluble drugs prepared by electrospinning (ES) with a water-soluble polymer, can offer significant improvements in drug dissolution for oral drug administration. However, when hygroscopic polymers, such as polyvinylpyrrolidone (PVP) are used, environmental moisture sorption can lead to poor physical stability on storage. This study investigated the use of polymer blends to modify PVP-based ES formulations of a model poorly soluble drug, fenofibrate (FF), to improve its physical stability without compromising dissolution enhancement. FF-PVP ES dispersions demonstrated clear dissolution enhancement, but poor storage stability against high humidity. Polymer blends of PVP with Eudragit E, Soluplus and hypromellose acetate succinate (HPMCAS), were selected because of the low intrinsic moisture sorption of these polymers. The drug-polymer and polymer-polymer miscibility study revealed that FF was more miscible with Eudragit E and Soluplus than with PVP and HPMCAS, and that PVP was more miscible with HPMCAS than Eudragit E and Soluplus. This led to different configurations of phase separation in the placebo and drug-loaded fibres. The in vitro drug release data confirmed that the use of PVP-Eudragit E retained the dissolution enhancement of the PVP formulation, whereas PVP-Soluplus reduced the drug release rate in comparison to FF-PVP formulations. The moisture sorption results confirmed that moisture uptake by the polymer blends was reduced, but formulation deformation occurred to phase-separated blend formulations. The data revealed the importance of miscibility and phase separation in understanding the physical stability of the ES fibre mats. The findings provide insight into the design of formulations that can provide dissolution enhancement balanced with improved storage stabilityPeer reviewedFinal Accepted Versio

DEVELOPMENT OF A TABLET FORM OF LIU WEI DI HUANG EXTRACT

Objective: Develop an effective and stable tablet form of Liu Wei Di Huang (LWDH).Methods: LWDH extract was obtained by decoction (TC) and reflux with water (WR). Extracts were concentrated and analyzed by HPLC-PDA using loganin as the bioactive marker. Adsorbents, tablet strength and friability, and tablet quality and stability were evaluated.Results: Extraction of LWDH formula from raw materials using WR yielded higher concentrations of loganin than TC. The best formulation of LWDH tablets included Avicel®PH101, corn starch, purified talcum, magnesium stearate and Cab-osil® with about 97.40% of the label amount of active marker. Excluding moisture from the product reduced marker degradation, suggesting a product shelf life 12+months. Finished tablets were uniform in weight, friability, disintegrated in<30 min, had good microbial and heavy metal contamination safety profiles and was stable.Conclusions: Extraction of LWDH formula using reflux with water produces higher yields than decoction. A suitable tablet formulation consists of dried water extract (38.83%), corn starch (29.13%), Avicel®PH101 (29.13%), purified talcum (0.97%), magnesium stearate (0.97%) and Cab-osil® (0.97%) prepared by wet granulation. Excluding moisture from the product reduces product degradation, suggesting a shelf life of 12+months. LWDH tablets avoid traditional formulation problems (high dosages, unacceptable taste and odor, lack of product uniformity, contamination with microorganisms and heavy metals), and are a good alternative for patients and TCM practitioners.Â

Characterization of hydrophilic polymers as a syringe extrusion 3D printing material for orodispersible film

The application of hydrophilic polymers in designing and three-dimensional (3D) printing of pharmaceutical products in various dosage forms has recently been paid much attention. Use of hydrophilic polymers and syringe extrusion 3D printing technology in the fabrication of orodispersible films (ODFs) might hold great potential in rapid drug delivery, personalized medicine, and manufacturing time savings. In this study, the feasibility of 3D-printed ODFs fabrication through a syringe extrusion 3D printing technique and using five different hydrophilic polymers (e.g., hydroxypropyl methylcellulose E15, hydroxypropyl methylcellulose E50, high methoxyl pectin, sodium carboxymethylcellulose, and hydroxyethylcellulose) as film-forming polymers and printing materials has been investigated. Rheology properties and printability of printing gels and physicochemical and mechanical properties of 3D-printed ODFs were evaluated. Amongst the investigated hydrophilic polymers, sodium carboxymethylcellulose at a concentration of 5% w/v (SCMC-5) showed promising results with a good printing resolution and accurate dimensions of the 3D-printed ODFs. In addition, SCMC-5 3D-printed ODFs exhibited the fastest disintegration time within 3 s due to high wettability, roughness and porosity on the surface. However, the results of the mechanical properties study showed that SCMC-5 3D printed ODFs were rigid and brittle, thus requiring special packaging to prevent them from any damage before practical use

Towards controlling the crystallisation behaviour of fenofibrate melt: triggers of crystallisation and polymorphic transformation

Fenofibrate (FEN) is a dyslipidemia treatment agent which is poorly soluble in water. FEN has tendency to form polymorphs and its crystallisation behaviour is difficult to predict. The nucleation process can be initiated by mechanical disruption such as ball milling or surface scratching which may result in different crystallisation behaviour to that observed in the unperturbed system. This study has obtained insights into the controllability of FEN crystallisation by means of regulating the exposed surface and growth temperatures during its crystallisation. The availability of an open top surface (OTS) during the crystallisation of the FEN melt resulted in a mixture containing FEN form I and IIa (I ≫ IIa) at room temperature, and in the range 40 to 70 °C. Covering the surface led to significant increases in the yield of form IIa at room temperature and at 40 and 50 °C. These temperatures also yielded the highest amount of form IIa in the OTS samples whilst crystallisation at 70 °C led to only FEN form I crystals regardless of the availability of the free surface. The metastable FEN form IIa transforms to the stable form I under the influence of a mechanical stress. Additionally, the introduction of OTS before the completion of crystallisation of form IIa led to a ‘switch’ of from IIa growth to form I. This study demonstrates that the polymorph selection of FEN can be obtained by the manipulation of the crystallisation conditions

3D inkjet printing of tablets exploiting bespoke complex geometries for controlled and tuneable drug release

A hot melt 3D inkjet printing method with the potential to manufacture formulations in complex and adaptable geometries for the controlled loading and release of medicines is presented. This first use of a precisely controlled solvent free inkjet printing to produce drug loaded solid dosage forms is demonstrated using a naturally derived FDA approved material (beeswax) as the drug carrier and fenofibrate as the drug. Tablets with bespoke geometries (honeycomb architecture) were fabricated. The honeycomb architecture was modified by control of the honeycomb cell size, and hence surface area to enable control of drug release profiles without the need to alter the formulation. Analysis of the formed tablets showed the drug to be evenly distributed within the beeswax at the bulk scale with evidence of some localization at the micron scale. An analytical model utilizing a Fickian description of diffusion was developed to allow the prediction of drug release. A comparison of experimental and predicted drug release data revealed that in addition to surface area, other factors such as the cell diameter in the case of the honeycomb geometry and material wettability must be considered in practical dosage form design. This information when combined with the range of achievable geometries could allow the bespoke production of optimized personalised medicines for a variety of delivery vehicles in addition to tablets, such as medical devices for example

Physical stabilization of low-molecular-weight amorphous drugs in the solid state: a material science approach

Use of the amorphous state is considered to be one of the most effective approaches for improving the dissolution and subsequent oral bioavailability of poorly water-soluble drugs. However as the amorphous state has much higher physical instability in comparison with its crystalline counterpart, stabilization of amorphous drugs in a solid-dosage form presents a major challenge to formulators. The currently used approaches for stabilizing amorphous drug are discussed in this article with respect to their preparation, mechanism of stabilization and limitations. In order to realize the potential of amorphous formulations, significant efforts are required to enable the prediction of formulation performance. This will facilitate the development of computational tools that can inform a rapid and rational formulation development process for amorphous drugs.Peer reviewe

The effects of SOY extract nutraceuticals on postmenopausal women’s health: A randomized, double-blind, placebo-controlled trial

Postmenopausal women experience physiological changes due to estrogen decline, affecting skin aging, bone health, and quality of life. The present study investigated the effects of the soy extract nutraceutical (SOY) product on facial skin health, bone turnover markers, menopausal symptoms, and quality of life in postmenopausal women by means of a randomized controlled trial. The effects of the product on lipids profiles, glucose levels, and insulin parameters were also explored. Participants received either the SOY product (n = 50) or a placebo (n = 50) for 12 weeks. The results showed significant improvements in facial skin wrinkle and bone turnover markers in the SOY group. While no major differences were observed in menopausal symptoms and quality of life between groups, the SOY group exhibited a significant reduction in total cholesterol levels. This study underscores the SOY product’s potential in addressing facial skin aging, bone health, and cholesterol management in postmenopausal women

A New Low Melting-point Polymorph of Fenofibrate Prepared via Talc Induced Heterogeneous Nucleation

Fenofibrate is one of the most commonly prescribed hyperlipidemia agents. Despite its high lipophilicity and ultralow aqueous solubility, most commercially available formulations use micronized crystalline fenofibrate form I, which has a low dissolution rate and poor oral bioavailability. Little is known about the crystallization of other polymorphs from supercooled amorphous fenofibrate. This study reports a new fenofibrate polymorph (form III) obtained via a controlled heterogeneous nucleation method using low quantity (1% w/w) of the generally recognized as safe (GRAS) oral pharmaceutical excipient talc. Form III has a low melting point of 50 °C, and crystallization of form I immediately occurs after the melting of form III. The microscopic, thermal, and spectroscopic characterizations of form III confirmed the distinct molecular packing difference between the new form and other known forms. The discovery of this new form will enrich the understanding of the molecular behavior of fenofibrate and bring useful insights into the role pharmaceutical excipients in selective crystallization of pharmaceutical active ingredient