Crystallization inhibition of active ingredients by electrospinning

An advantage of drug encapsulation in electrospun fibers is that the spinning process reduces drug crystallization. Drug crystallization has been said to make the drug delivery system unstable and causes a drop in the drug loading efficiency and unpredictable release behavior [Kwak et al 2017]. Using water soluble fish gelatin (FG), Kwak et al (2017) demonstrated the lack of crystallization and the rapid release of caffeine in electrospun FG. For solvent cast FG film, with only 0.8 w/v% of caffeine added, spherical crystalline nucleus can be seen. Electrospun fibers in contrast can take up to 2% loading in FG without any disruption to the smooth fiber morphology.

Borbas used sulfobuthyletherβ-cyclodextrin (SBEβCD) for encapsulation of aripiprazole (ARP) in the presence of citric acid in poly(ethylene oxide) (PEO) solution for electrospinning into fibers. The combination was optimized such that the lowest possible PEO concentration for fiber production was used as PEO may retard the dissolution process. Comparing the dissolution time taken for the ARP loaded PEO, pure ARP and mixture of ARP and SBEβCD, it takes only 3 minutes for complete dissolution of ARP loaded PEO electrospun fibers. The mixture only released 20% of ARP for the same duration while dissolution of pure ARP was less than 3% after 60 minutes. Faster release rate of ARP in electrospun fibers is because the drug remains in an amorphous state instead of thermodynamically stable crystalline form. ARP encapsulated in electrospun PEO fibers was found to remain in amorphous state even after 3 months.

Many active compounds have poor aqueous solubility and this limit their application as therapeutic drugs and supplements. Sriyanti et al (2018) attempted to overcome this constraint by using electrospun fibers as a carrier for α-Mangostin which is a major active compound of mangosteen (Garcinia mangostana L.) pericarp extract (MPE) with potent antioxidant activity. Polyvinylpyrrolidone (PVP) was used as the carrier due to its low toxicity and good water solubility. Electrospun α-mangostin loaded PVP fibers was found to be amorphous compared to the crystalline form of pure α-mangostin powder. Release of α-mangostin was fast in the PVP nanofibers with over 90% released in an hour while less than 35% were released from its powder form. The radical scavenging activity of the α-mangostin released from the electrospun fibers was good with a IC₅₀ value of 55-67 µg/ml which was slightly lower than pure α-mangostin powder with value of 69 µg/ml. Sipos et al (2019) showed that the crystalline drug, aceclofenac when loaded in triethanolamine-containing polyvinylpyrrolidone (PVP) and electrospun into nanofibers, aceclofenac is present in an amorphous state. In its pure form, dissolution rate was 51% at the first minute and 85% at 3 min in phosphate buffer solution. However when it is in the amorphous state in triethanolamine-containing polyvinylpyrrolidone (PVP) nanofibers, the drug release from the nanofibrous web is almost immediate and complete within a minute. Such rapid dissolution was attributed to the amorphous state of the drug, hydrophilic nature of PVP and high surface area of nanofibers. Ye et al (2020) investigated the use of core-shell electrospun fibers for delivery of the drug, emodin which has been shown to be effective against Methicillin-resistant Staphylococcus aureus (MRSA). In its unencapsulated form, emodin is crystalline and hydrophobic which limits its usage. When emodin was blended into poly(vinylpyrrolidone) (PVP) solution and electrospun in a core-shell fiber structure, it existed in an amorphous form. To blend emodin with PVP, a mixture of acetone and N,N-Dimethylacetamide (DMAC) was used as the solvent. The emodin/PVP forms the core and cellulose acetate (CA) forms the shell in the coaxial electrospinning setup. Subsequent tests post electrospinning showed that the emodin has been transformed from a crystalline raw form to an amorphous form. The disruption of the emodin crystals may be due to strong intermolecular interactions between emodin and PVP molecules resulting in amorphous form in the nanofibers. In vitro drug release test showed that the dissolution rate of emodin from the nanofiber membranes was significantly higher than that of raw crystalline emodin. At 156 h, more than 99% of emodin has been released from the electrospun membrane but only 31% was dissolved from raw emodin. Porous and thin electrospun mats containing other ingredients such as mint or medications may offer advantages over off-the-shelf oral dissolving film strips. Ning et al (2021) used core-shell electrospinning with non-electrospinnable sucralose and low molecular weight polyvinylpyrrolidone (PVP) as the shell and the drug diclofenac sodium (DS) and high molecular weight PVP as the core. Both sucralose and DS are crystalline in its pure solid form. However, with the addition of PVP and electrospinning, sucralose and DS was able to retain its amorphous state after electrospinning to form fibers. Sucralose and DS were found to form secondary bonds with PVP molecules and these may have helped to retard crystalization during the electrospinning process. Further, the rapid vaporization during electrospinning also reduces the time available for crystallization of sucralose and DS molecules. The amorphous state of the active ingredients contributed to the rapid dissolution and release of DS in the presence of water with the electrospun membrane completely disappearing within 16s. However, DS powder which is crystalline took almost an hour for complete dissolution.

To appreciate the advantages of using electrospinning for drug release, it is useful to compare with other methods of encapsulation and introduction. Szabo et al (2021) compared the dispersion of amorphous solid dispersions (ASDs) made up of poorly soluble spironolactone (SPIR) and poly(vinylpyrrolidone-co-vinyl acetate) using spray drying and electrospinning. Both processes require the use of solvents for the dissolution of the active compounds. The release of spironolactone was carried in 0.1 N HCl dissolution media at a temperature of 37 °C. Both electrospun and spray dried samples dissolved quickly. Electrospun samples released more than 90% of its load in 20 min while the amount of SPIR released by spray dried samples plateaus at about 60%. The total amount of SPIR released by spray dried samples was the same as micronized crystalline SPIR. SPIR encapsulated using electrospinning and spray drying showed an amorphous state. However, spray dried SPIR contains 5 to 7 % crystalline nuclei which could have induced quick crystallization upon contact with media while electrospun samples contained less than 1% crystalline nuclei. Additional tests showed that slow evaporation rate of the solution such as in solvent casting method leads to greater crystallinity and hence lower dissolution of SPIR in the media. Electrospinning is also known for its fast solvent vaporisation rate and this may have contributed to its lower count of crystalline nuclei. Another factor would be the electric field effect that helps to maintain dispersion of SPIR. Electrospraying of SPIR solution was also found to yield better dissolution compared to spray dried samples which showed that electric field may have played a part.

Drugs loaded in electrospun carrier polymers may be amorphous immediately after the fibers have been collected. However, storage over a period of time may lead to re-crystallization of the drugs. Uhljar et al (2022) did a comparison of the ciprofloxacin (CIP)-loaded polyvinylpyrrolidone (PVP) electrospun fibers using a drum surface electrospinning setup and single nozzle electrospinning setup. At the same concentration, the single nozzle electrospun fibers have an average diameter of 323 nm while the drum surface electrospun fibers have an average diameter of 1167 nm. Comparing the crystallinity of the CIP in the fibers over a period of time up to 26 months, it was shown that the CIP-loaded PVP fibers from single nozzle electrospinning showed re-crystallization at the 8th month. However, for the CIP-loaded PVP fibers from the drum surface electrospinning setup, the CIP remained amorphous at 26 months. Given that PVP is water soluble and that PVP fibers from the drum surface electrospinning have a much larger diameter than the fibers from single nozzle electrospinning, it is likely that there is less influence of room-condition humidity on fibers with larger diameter. The increase in the crystallinity of CIP in the fibers invariably reduces the release rate of CIP.

It is not always that drugs in electrospun fibers will show lower crystallization than film. Tornello showed that with encapsulation of embelin in poly(ε-caprolactone) (PCL), both electrospun form and cast film form showed significant reduction in the crystallinity. Although scanning electron micrograph image showed rough surface on cast film containing embelin while electrospun fibers containing embelin remains relatively smooth, embelin crystallinity in cast film is lower than that in electrospun fibers. Seif et al (2015) found that the solvent polarity and its interaction with the drug has a major impact on its crystallization while electrospinning parameters only have a minor influence. Shi et al (2013) showed that with artemisinin (ART) loaded into cellulose acetate (CA) and poly(vinyl pyrrolidone) (PVP) solution for electrospinning, ART crystals were formed. However, if a co-axial setup was used instead with ART dissolved in cellulose acetate (CA) solution in the core and PVP as the shell material, ART remains in the amorphous state post electrospinning and remained in amorphous state after 6-month storage. Stability of ART in amorphous state was attributed to hydrogen bonding between the drug and CA.

Left. Scanning electron micrograph of electrospun PCL/Embelin (surface exposed to air; × 3000). Right.Scanning electron micrograph of PCL/Embelin cast film [Tornello et al 2012]