Dextrin nanocomposites and deep eutectic solvents as matrices for solid dosage forms

Abstract

Controlled-release formulations for pesticide applications act as depot systems that continuously release the active ingredients into the environment over a speci ed period, usually from months to years. However, some applications require fast-dissolving drug delivery. The interest of this research is in fast-release of water-insoluble pesticides into aquatic environments. This study considered the use of dextrin starch and urea eutectics as fast release, solid dosage carrier forms that contain an active ingredient. The chosen active for this study is an acaricide called amitraz (N-methylbis-(2,4-xylyliminomethyl)- methylamine). The focus is on matrix-based dosage forms such as tablets, granules or bres that either disintegrate or dissolve to release a water-insoluble active. These types of dosage forms can be fabricated using processes such as lyophilisation, spray drying, solvent casting, hot melt extrusion, compression moulding, wet granulation, compaction and electrospinning. A simple melt-casting procedure has been discussed in the present work. Dextrin is a water-soluble form of partially hydrolysed starch and is a promising candidate matrix material for dissolving solid dosage forms. The molecular weight of the dextrin was analysed with MALDI-TOF methods and rheological relations. Glycerolplasticized thermoplastic dextrin-based nanocomposites were prepared with a twin-screw extrusion-compounding process. The nano llers included a layered double hydroxide (LDH), cellulose nano bres (CNF) and stearic acid. The time-dependent retrogradation of the compounds was monitored by X-ray di raction (XRD) and dynamic mechanical thermal analysis (DMA). XRD showed that the inclusion of stearic acid in the formulations led to the formation of an amylose-lipid complex and a stable crystallinity during ageing. Dissolution rates in water for samples containing dextrin starch, were characterised using an iodine indicator and UV-visible spectroscopy. High pressure di erential scanning calorimetry (HPDSC) indicated that the addition of stearic acid led to the formation of amylose-lipid complexes (ALC's). An additive system containing stearic acid and CNF was deemed suitable for compounding with amitraz. Compounding at temperatures above the melting point of the latter led, on dissolution in water, to the release of much ner particles of the acaricide, which was con rmed with particle size analysis (PSA). The addition of the acaricide caused an apparent increase in the dissolution rate of the thermoplastic dextrin. Two eutectic urea systems were considered for casting with amitraz. A eutectic system of urea and acetamide was found to display a melting point of 44 C at a 37 wt.% urea composition. The other system consisting of urea and 1,3-dimethylurea displayed a eutectic point at 32 wt.% urea composition which melted at 59 C. Di erential scanning calorimetry (DSC), however, con rmed a melting point depression due to a high moisture content caused by the compounds high hygroscopicity. The endotherm of the sample containing no excess moisture showed a melting point of 70 C. The 1,3-dimethylurea system was deemed suitable for casting with amitraz. XRD of the eutectic composition indicated a small amount of co-crystallisation. The samples were cast as disks of various diameters while keeping the height of the disks constant. The creation of the cast disks showed automatic generation of a nely dispersed form of the active through the process of melting the deep eutectic solvent, the dissolution of the active and its phase separation on cooling and solidi cation of the eutectic. This implies that ne grinding of the actives might not be necessary. Eutectic casts containing 20 wt.% amitraz dissolved at a slower rate than casts not containing the hydrophobic active ingredient. The advantageous features of these casts were exempli ed using the acaricide incorporated into the urea & 1,3-dimethylurea eutectic. This work provides two safe, biodegradable and water soluble materials for use as a matrix to contain active ingredients. One material, the eutectic organic salt casts, can be produced at low temperatures (<100 C) and can be directly cast into storage containers. The complete dissolution of the cast compounded with a hydrophilic active is rapid (4-6 min). The second material, a thermoplastic dextrin, was melt compounded in an extruder at temperatures not exceeding 120 C. This compound containing 20 wt.% of the active dissolved over a 12 hour period. Dextrin, known to be widely used as an adhesive, will aid in the adhesion of the active ingredient to the surface where it must be used.