(198q) Critical Process Parameters for the Manufacture of Dry Drug Nanoparticle- Carrier Particle Nanocomposite Powders | AIChE

(198q) Critical Process Parameters for the Manufacture of Dry Drug Nanoparticle- Carrier Particle Nanocomposite Powders


Silva, M., University of Limerick
Hudson, S., University of Limerick
Rasmuson, A., KTH Royal Institute of Technology

Anti-solvent precipitation was employed to generate nanoparticles of active pharmaceutical ingredients (APIs) in a fast, cost and energy efficient way to solve the well reported problem of poor solubility and slow dissolution rates in aqueous media of many drugs in the pharmaceutical developmental pipeline1. Surfactant and polymeric additives are frequently used to stabilize the nanoparticles. However, the stabilizing effect of additives at minimal concentrations is not often reported. To increase their shelf life, particles are often dried to solid state via traditional methods such as freeze-drying or spray drying. Recently, a more novel carrier particle mediated filtration for the isolation of nanoparticles to the dried state has been proposed.

Carrier particle mediated filtration involves the attachment of the precipitated drug particles to the surface of the carrier particles followed by filtration. The presence of stabilisers can impact the level of nanoparticle attachment. Khan et al. first used insoluble dibasic calcium phosphate carrier particles to isolate ibuprofen and glibenclamide nanosuspensions prepared by either wet milling or antisolvent precipitation in the presence of soluble stabilizers2. 90 – 95 % isolation was achieved via filtration and the dried nanocomposite powders showed a rapid dissolution rate of 90% within the first 5 min, comparable to the original aqueous nanosuspensions. However very low 0.35 % (w/w) maximum drug loading was achieved in this process. Tierney and Bodnar et al developed a method to stabilize and isolate nanoparticles in the absence of soluble stabilizers where the insoluble carrier particle montmorillonite clay (MMT) was present within the antisolvent before nucleation. Fast dissolving fenofibrate, mefenamic acid and dalcetrapib – MMT nanocomposite powders were isolated with up to 9.1 %, 4.8 % and 20.9 % API loading respectivelyly3, 4. Kumar et al. used the same antisolvent precipitation method and convert the batch process into a semi continuous method to produce gram scale valsartan nanocomposite suspensions in a 60 ml mixing chamber using the previously used MMT clay carrier particles, again present during nucleation and in the absence of soluble stabilsers. They isolated the powders to dryness using a simple in-line Buchner funnel setup5. A limitation of this approach is that the exact size of the API nanoparticles cannot be determined.

The study presented here probes the impact of lowering additive concentration on the stabilization of drug nanoparticles and the subsequent effectiveness of carrier particle mediated isolation to dryness. A semi-continuous method to produce API nanosuspensions in the presence of additives and the optimal method to subsequently attach the nanoparticles to MMT was developed. Using this approach, the production of fast dissolving nanocomposite powders, with the size of the nanoparticles clearly defined and measured, was achieved using batch and semi-continuous processes. Dalcetrapib (DCP) was used as the model API for this work.


Preparation of DCP nanosuspensions:

Dalcetrapib (DCP) nanosuspensions were prepared via a batch liquid antisolvent precipitation method where methanol was used as solvent and water as antisolvent. A portion of DCP solution was taken by Eppendorf pipette and quickly introduced to antisolvent solution (under the surface) containing the polymeric additive polyvinylalcohol (PVA) and surfactant additive sodium docusate (DOSS) at constant temperatures and stirring rates throughout the precipitation process. Milky suspensions were formed instantly in all experiments. Various additive concentration ranging from 1 mg/ml to 0.01 mg/ml for PVA and DOSS respectively were explored.

Continuous DCP nanosuspension production was done via the schematic setup showed in Figure 1, which consists of a jacketed vessel precipitation chamber to maintain temperature connected with an antisolvent reservoir via peristaltic pump and a DCP methanol solution via 20 ml syringe pump. The flow of antisolvent and DCP solution was started simultaneously and mixed inside the empty precipitation chamber at constant stirring rate. These flow rates were chosen based on the optimal antisolvent/solvent ratio from the batch process. The produced nanosuspensions first filled the precipitation chamber and overflowed continuously to a collection vessel that was placed inside a water bath at constant temperature with stirring. Particle size measurements for DCP nanosuspensions were carried out on a Malvern Zetasizer Nano ZPS or Mastersizer 3000 system.

Isolation and drying of dalcetrapib nanoparticles from suspension:

Montmorillonite clay (MMT) was used as insoluble carrier particles to isolate the DCP nanoparticles from suspension. Dry or, pre wetted MMT carrier particles corresponding to targeted loading were added to DCP nanosuspensions prepared in the presence of high (1 mg/ml PVA and 0.5 mg/ml DOSS) or low (0.03 mg/ml PVA and 0.03 mg/ml DOSS) concentration of additives with the resultant sample then stirred at constant temperature and rpm for set periods of attachment time (AT), Table 1. The samples were then isolated by vacuum-filtration and the filtered cakes were dried in a fume hood at ambient temperature and pressure.

Dissolution rate determination:

The dissolution media (DM) used for DCP was ‘0.1 M HCl solution and 2 g/L NaCl, and 2.5 g/L SDS’, respectively. Dissolution testing of ‘as received’ DCP and DCP nanocomposites were carried out under sink conditions at a constant temperature and stirring rate. At specific time intervals, aliquots were withdrawn using preheated plastic syringes and filtered through PTFE syringe filters. The drug concentration in the dissolution media was quantified using UV–Visible spectrophotometry at wavelength 244 nm.

Result and discussion:

Antisolvent precipitation of DCP at 5 ℃ in the presence of a surfactant additive, sodium docusate (DOSS) and a polymeric additive, polyvinyl alcohol (PVA), at 0.5 mg/mL and 1 mg/mL respectively, generated a stable suspension in the nanometre range for up to 30 mins, Figure 2. Lowering the concentration to 0.03 mg/ml for both additives produced a nanosuspension that was stable for up to 1 hour, Figure 2. Thus, lowering the concentration of both additives helped to stabilize the nanosuspension for a longer time. Also using the same lower additive concentration during a semi continuous antisolvent precipitation process was able to generate nanometre size DCP particles.

Isolation of DCP nanosuspensions prepared with high additive concentration using MMT carrier particles showed poor isolation and loading efficiencies, Table 1. A light milky filtrate was observed in this case indicating the presence of DCP nanoparticles in the filtrate and poor attachment to the MMT carrier particles. A clear filtrate was observed in the case of low additive concentrations indicating good attachment of the DCP nanoparticles to the MMT carrier particles. Thus, although higher additive concentrations interfered with the adsorption of DCP nanoparticles to the MMT surface, the presence of smaller amount of soluble additives stabilised the nanoparticles without interfering with attachment to the MMT surface. DCP nanocomposite isolation with dry or pre-wetted MMT particles and 10 minute or 3 hour attachment times (AT) was performed with a target 20 % drug loading. It was observed that both pre wetting or long attachment times were required to reach the target loading and maintain the fast dissolution rate, Table 1, and Figure 3. 30 and 40% DCP loadings were also achieved via the same procedure of pre wetting the MMT with dissolution rates similar to the 20% loaded nanocomposite powder observed.


Low concentrations of additives can produce drug suspensions with narrow particle size distributions with longer stability than higher concentrations and results in a better isolation efficiency during a liquid antisolvent precipitation production process followed by carrier particle mediated isolation to dryness. Pre-wetted and/or longer attachment times contribute to improved drug loadings and dissolution rates.


(1) Gigliobianco, M. R.; Casadidio, C.; Censi, R.; Di Martino, P. Nanocrystals of Poorly Soluble Drugs: Drug Bioavailability and Physicochemical Stability. Pharmaceutics 2018, 10 (3).

(2) Khan, S.; Matas, M. De; Plakkot, S.; Anwar, J. Nanocrystal Recovery by Use of Carrier Particles. 2014.

(3) Tierney, T.; Bodnár, K.; Rasmuson, Å.; Hudson, S. Carrier Particle Design for Stabilization and Isolation of Drug Nanoparticles. Int J Pharm 2017, 518 (1–2), 111–118.

(4) Bodnár, K.; Hudson, S. P.; Rasmuson, Å. C. Drug Loading and Dissolution Properties of Dalcetrapib-Montmorillonite Nanocomposite Microparticles. Org Process Res Dev 2020, 24 (6), 977–987.

(5) Kumar, A.; Ramisetty, K. A.; Bordignon, S.; Hodnett, B. K.; Davern, P.; Hudson, S. Preparation, Stabilisation , Isolation and Tableting of Valsartan Nanoparticles Using a Semi-Continuous Carrier Particle Mediated Process. Int J Pharm 2021, 597 (September 2020), 120199.