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The poor solubility and related low bioavailability are a major concern for a large number of small molecule drugs, both on the market and in development. Several formulation strategies exist to overcome this issue. Among them, particle engineering is of outmost importance. The aim of this work is to present the potential of Spray Flash Evaporation (SFE), a new technology for drug particle engineering. To assess the potential of SFE, we carried out a case study on the nano-crystallization of furosemide, a BCS class IV drug. A thorough characterization of the obtained nanocrystals is presented along with a study of dissolution which highlights the solubility improvement provided by nanocrystals produced via SFE technology. The obtained results show a particle size reduction when compared to the raw material, as well as an increase of the dissolution rate of 4.5-fold.

Recently, the intensified vibratory milling (IVM) has emerged as a viable milling technology known for its nanosizing and high-throughput potential. The extent of the heat generation is ambiguously discussed within the literature. For this reason, the impact of formulation and process parameters for both particle size reduction and heat generation, needs further investigation to develop robust processes using the IVM technology. For this reason, the impact on particle size and heat generation of three different process parameters: - bead-suspension ratio; milling time; and acceleration - as well as one formulation parameter - API concentration - was investigated by a one-variable-at-a-time approach. Further the effect of additional fixtures on the heat generation was noted. The data obtained in this work showed that if the impact on heat generation was taken into account, the process parameters could be fine-tuned to optimize the nano-sizing potential while containing a continuous milling process. A longer milling time and production of highly concentrated formulations were proposed as gentle optimisation steps for the herein presented comminution process. ispartof: International Journal Of Pharmaceutics vol:587 pages:119644-119644 ispartof: location:Netherlands status: published

New drug substances from early development are often poorly water-soluble, which causes poor bioavailability upon peroral administration and hampers drug administration through other routes such as the parenteral or ocular routes. One approach to improve drug solubility and administration flexibility is by wet milling to nanosize. Particle size reduction increases the surface energy which requires adequate stabilization by excipients. In this study, the practically water-insoluble miconazole was nanoground, and a variety of surface active and polymeric excipients were tested for their stabilizing effects. For efficient milling, two preformulation criteria had to be fulfilled: a relatively low contact angle (70 degrees ) and high dispersibility of the native drug particles in the milling medium. Hydroxypropylcellulose (HPC-LF) in combination with sodium dodecyl sulfate (SDS) stabilized best the miconazole nanosuspensions. A design of experiments was used to achieve drug particle mean sizes of 140-170nm by varying the concentrations of miconazole (5 and 20%, w/w), SDS (0.05 and 0.2%, w/w), and HPC-LF (1.25 and 5%, w/w). Further experiments revealed that minimal 0.0125% SDS and 3.125% HPC-LF were required for miconazole nanogrinding and nanosuspension stabilisation. Storage of the nanosuspensions at 5 degrees C for up to 6 months caused only minor changes, whereas storage at 25 degrees C resulted in particle agglomeration and single crystal growth. Altogether the study showed that excellent wetting of drug particles as well as their electrostatic and steric stabilization by excipients is necessary to produce stable nanosuspensions by nanogrinding.

Hydroxycamptothecin is a promising anticancer agent that possesses the ability to inhibit the growth of a wide range of human tumors. Owing to its poor solubility and instability, the pharmaceutical development and clinical utilization of hydroxycamptothecin have been limited. In the present study, a novel precipitation-combined high-pressure homogenization (PCH) technique was used to prepare hydroxycamptothecin nanosuspensions. Based on the homogenization pressure and number of cycles, the process with 10 cycles at 18,000 psi of homogenization pressure was found to be the most efficient method to achieve consistent particle size reduction. It was used to prepare nanosuspensions for characterization and evaluation of the formulation performance. Lyophilization of hydroxycamptothecin nanosuspensions, the shape and crystal form of the drug, and antiproliferative activity were also studied. The mean particle size (z-ave) of the reconstituted freeze-dried powder was small and uniform. The freeze-dried powder might be a good choice for intravenously administrating poorly soluble hydroxycamptothecin, which proved to have higher cytotoxicity against the cancer cells than hydroxycamptothecin injections (p0.001). Overall, these studies have demonstrated that the PCH technique can be used successfully to prepare hydroxycamptothecin nanosuspensions.

According to the present theory of oral absorption, in the case of solubility limited absorption, the absorbed amount would not increase despite an increase in dose or a decrease in particle size. However, many experimental observations suggested that the absorbed amount was often increased (though sub-proportionally) as the dose strength increased. In addition, the particle size reduction was often effective to increase the absorbed amount even in the case of solubility limited absorption. Since an increase of the dose strength and a decrease of the particle size cause no or little change in solubility and the mean intestinal transit time, effective intestinal membrane permeability ( P eff ) should have changed. The previous theory postulated that drug particles do not exist in the unstirred water layer (UWL) which is adjacent to the intestinal membrane. However, many reports suggested that nano- to micro-scale drug particles existed in the UWL. In this case, the effective thickness of the UWL ( h eff ) could be smaller than the nominal thickness, resulting in an increase of P eff . In the present study, h eff was simply calculated assuming that the reduction of h eff is in proportion to the surface area of drug particles in the UWL. When the particle drifting effect was taken into account, the discrepancy between the theoretical calculation and experimental observations was reduced. It was suggested that when the dose (mg)/particle diameter (μm) ratio exceeds 20, the particle drifting effect would become significant.

Nanonization of the poorly water-soluble drugs is a promising strategy to improve dissolution and oral bioavailability. To stabilize the drug nanosuspensions, stabilizers are usually used; however, the use of common stabilizers is limited by weak stabilization effect and toxicological concerns for long-term treatment. The present work was to investigate the potential of food proteins as novel safe stabilizers for nanosuspensions using indomethacin as a model drug. The nanosuspensions stabilized by food proteins (soybean protein isolate, whey protein isolate and β-lactoglobulin) were prepared by the nanoprecipitation–ultrasonication method. The particle size could be easily reduced to 100–400 nm with bimodal particle-size distribution through monitoring the preparative variables. The exposure of buried hydrophobic moieties due to heat-denaturation and subsequent adsorption onto the surface of drug particles was assumed to contribute to their efficient stabilization effect. In comparison with conventional stabilizers, food proteins are superior in stabilization efficiency. The dissolution was enhanced significantly owing to particle size reduction. The protein-stabilized nanosuspensions could be easily freeze-fried and reconstituted into nanosuspensions, keeping the original mean particle size and particle-size distribution. It is concluded that the three denatured proteins perform as efficient stabilizers for indomethacin nanosuspensions.

Nanosizing is one of the most important drug delivery platform approaches for the commercial development of poorly soluble drug molecules. The research efforts of many industrial and academic groups have resulted in various particle size reduction techniques. From an industrial point of view, the two most advanced top-down processes used at the commercial scale are wet ball milling and high pressure homogenization. Initial issues such as abrasion, long milling times and other downstream-processing challenges have been solved. With the better understanding of the biopharmaceutical aspects of poorly water-soluble drugs, the in vivo success rate for drug nanocrystals has become more apparent. The clinical effectiveness of nanocrystals is proven by the fact that there are currently six FDA approved nanocrystal products on the market. Alternative approaches such as bottom-up processes or combination technologies have also gained considerable interest. Due to the versatility of nanosizing technology at the milligram scale up to production scale, nanosuspensions are currently used at all stages of commercial drug development, Today, all major pharmaceutical companies have realized the potential of drug nanocrystals and included this universal formulation approach into their decision trees.