Comparative Evaluation of Four Structurally-Related Profens for Nanoparticle Formulation

Abstract

Purpose: Our previous studies have demonstrated the utility of flash nanoprecipitation (FNP) for consistent production of drug nanoparticles through optimization of formulation and processing variables [1-3]. To assess the general applicability of the findings from these studies to other drug materials, the present study has similarly examined polymer-stabilized nanoparticle (NP) production by FNP for four structurally-related nonsteroidal anti-inflammatory drugs (NSAIDs), namely, ibuprofen (IBU), flurbiprofen (FLU), ketoprofen (KET) and loxoprofen (LOX), all of which belong to the chemical class of 2-arylpropionic acid derivatives (i.e., profen). Additionally, to determine whether the properties of the formulated nanoparticles are also dependent on the chemical structure, or more specifically, intrinsic physicochemical properties of incorporated drug, the physical properties of the various profen NPs produced under the same optimized conditions have been correlated with three intrinsic solution properties (i.e., water solubility, pKa and log P) of the corresponding profens. These physicochemical parameters have been selected for the correlation analysis mainly because of their relevance to the properties of the nanoparticles (i.e., particle size, encapsulation efficiency and drug loading) being studied. Furthermore, the use of structurally related compounds within the same chemical class in the present study has the special advantage of ensuring close similarity in the mode of physical interaction between each drug and the co-precipitating copolymer, thus eliminating this potential confounding factor in the correlation analysis. Methods: NPs of each profen drug were prepared by FNP using a four-stream multi-inlet vortex mixer (MIVM) as reported previously [1] with a feeding polyethylene glycol-b-poly(DL-lactide) (PEG-PLA) 2k-10k concentration at 10 mg/ml in acetone. The profens were employed at either a fixed feeding concentration of 10 mg/ml in the organic stream or concentrations that would yield the same supersaturation level in the final 5% v/v acetone-water mixture. The particle size and polydispersity index (PI) of the resulting profen NPs were analyzed by dynamic light scattering (DLS). Encapsulation efficiency (EE) and drug loading (DL) were determined by HPLC. Physical stability was monitored by visual examination and measurement of the change in particle size with time. Results: As shown in Figure 1, at the same feeding drug concentration, the particle sizes of the various profens drugs followed in ascending order of LOX < KET < IBU < FLU. Employing multiple linear regression analysis, aqueous solubility (SOL), pKa and log P values of the profens were found to be important determinants of the particle size of resulting NPs (p < 0.05, R2 = 0.997); an increase in log P or pKa or a decrease in SOL led to an increase in particle size of NPs. The relative importance of these intrinsic solution properties in influencing particle size, as determined by the t values, followed in descending order of log P > pKa > SOL. At the same feeding drug concentration, a lower SOL of the profen tended to produce NPs with higher DL and EE. At the same supersaturated ratio, the particle sizes of different profen NPs were not significantly different from one another but appeared to follow the same rank order as the solubilities of the corresponding profens (i.e., KET>IBU>FLU) (Figure 2), whereas EE varied inversely with SOL. With the feeding drug concentration and mixing rate being maintained at 10 mg/ml and Re ≈ 4,500 respectively, increasing the stabilizer (polymer) mass fraction (Xs) led to a decrease in particle size down to a constant level from Xs = 0.25 onward (Figure 3), indicating that particle size is independent of stabilizer content beyond this critical limit. Conclusion: The particle sizes of the various profen NPs have been shown to be governed by all three intrinsic physicochemical properties (i.e., aqueous solubility, pKa and log P) of incorporated profen, while DL and EE of the various NP samples depend predominantly on the water solubility of the profen. The critical drug-to-stabilizer ratio for particle size control of the different NP samples was around 4:1. References: 1. Chow, S.F., Sun C.C., Chow A.H.L., Assessment of the relative performance of a confined impinging jets mixer and a multi-inlet vortex mixer for curcumin nanoparticle production. Eur. J. Pharm. Biopharm, 2014. 88: 462-471. 2. Wan, K.Y., et al., Impact of molecular rearrangement of amphiphilic stabilizers on physical stability of itraconazole nanoparticles prepared by flash nanoprecipitation. Int. J. Pharm, 2018, 542, 221-231. 3. Chow, S.F., et al. Development of highly stabilized curcumin nanoparticles by flash nanoprecipitation and lyophilization. Eur. J. Pharm. Biopharm, 2015, 94: 436-449