University of Limerick
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Carrier particle mediated stabilization and isolation of drug nanoparticles in a batch and continuous process

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posted on 2023-02-24, 19:57 authored by Ajay KumarAjay Kumar
Drug nanoparticles are a promising solution to the challenging issues of low dissolution rates and erratic bioavailability due to their greater surface area/volume ratio resulting in improvement in dissolution rate and bioavailability. The central purpose of the study carried on this thesis was to prepare, stabilize and isolate nanoparticles of poorly water-soluble active pharmaceutical ingredients (APIs) into a dried form with the help of clay carrier particles. Isolation of nanoparticles from suspension into the dried state is crucial to avoid the problems of aggregation and Ostwald ripening. In this study nanoparticles (NPs) of four poorly watersoluble active pharmaceutical ingredients (APIs) (valsartan (Val), clozapine (CLO), curcumin (CUR) and carbamazepine (CBMZ) with zeta potentials -42.5±1.4, -28.5 ±2.5, -33±1.5 and - 13±1.5 mV respectively) were produced, stabilised and isolated into the solid-state with the help of montmorillonite (MMT) clay carrier particles. The nanoparticles of valsartan (50 nm), clozapine (27nm), curcumin (170 nm) and carbamazepine (30 nm) were produced and stabilized in suspension using a reverse antisolvent precipitation technique in the presence of ‘as received’ MMT carrier particles (~30 m) and/or MMT carrier particles whose surface had been slightly modified with a cationic protein, protamine sulphate salt (PA). The resulting nanoparticle carrier composites were isolated directly from suspension into a solid-state form by simple filtration followed by air-drying. The API dissolution rates from these dried NPcarrier composites were comparable with those of the respective polymer-stabilized API nanoparticles in suspension up to maximum valsartan, clozapine, curcumin and carbamazepine loadings of 33.3%, 23%, 21.8% and 33.3 % (w/w) respectively confirming that the high surface area of the nanoparticles is retained during the adsorption and drying processes. The dissolution profiles of these nanoparticles from their respective MMT/PA-MMT nanocomposites were shown to be influenced by parameters such as the zeta potential of the API nanoparticles, the degree of PA functionalization, and the API loading on the carrier particle system. It has been found that for API nanoparticles with zeta potential more negative than ca. -25 mV, prior functionalisation of MMT’s surface with protamine (PA) was needed in order to preserve the fast API nanosuspension-like dissolution rates at higher API loadings. For these APIs, the optimal loading of PA on MMT was consistently around 4 mg/g, which likely helped to limit aggregation of the API nanoparticles thus facilitated the enhanced dissolution profiles of these API nanoparticles at higher loadings from the dried state. By contrast, API nanoparticles with zeta potentials less negative than ca. –25 mV did not require the MMT modification with PA in order to maintain enhanced dissolution profiles at high API loadings. Following the above studies, the technical feasibility of transforming this batch processing method of antisolvent precipitation, stabilisation and isolation for API nanoparticles into continuous processing was investigated. Specifically, a novel process was developed for the continuous carrier particle mediated stabilization and isolation of valsartan nanoparticles in a solid-state form using MMT as a carrier particle. Nanoparticles of valsartan (51±1 nm) were successfully prepared, stabilized and isolated into the dried form by this continuous route. The dissolution profile of the isolated valsartan nanocomposite solids was similar to that of valsartan nanocomposite solids produced via the corresponding batch mode process, confirming that the product quality is retained during the continuous processing of the nanoparticles. Furthermore, tablets produced via direct compression of the isolated valsartan nanocomposite solids displayed a dissolution profile comparable with that of the powdered valsartan nanocomposite material. The valsartan nanoparticles produced via this continuous process possessed shelf-life stability of >10 months (based on accelerated stability storage conditions of 313 K and 75% relative humidity for 2.5 months), thus indicating the long-term stability potential of valsartan nanocomposites produced via this carrier particle mediated continuous antisolvent precipitation, stabilisation and isolation process.



  • Faculty of Science and Engineering


  • Doctoral

First supervisor

Benjamin K Hodnett

Second supervisor

Sarah P. Hudson





Department or School

  • Chemical Sciences

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