Min Kyung Lee

Cryoprotectants for freeze drying of drug nano-suspensions: Effect of freezing rate

Drug nanoparticles are often prepared in a liquid medium, and a drying method such as freeze drying is used to convert them to an oral solid dosage form. When the dried form is reconstituted in an aqueous system, it may be redispersed to achieve its original particle size. The redispersibility of dried nanoparticles depends on the parameters of the freeze drying process. In this study, an apparatus with a freezing rate gradient was used to systematically investigate the effect of cryoprotectants on the redispersibility of nanoparticles as a function of freezing rate. Sucrose, lactose, mannitol, and polyethylene glycol were used as cryoprotectants for a naproxen nano-suspension. A fast freezing rate and a high cryoprotectant concentration were generally favored. However, under certain conditions, a slower freezing rate resulted in better redispersibility. This is probably because slow freezing can produce a more cryo-concentrated liquid phase, and the concentrated cryoprotectant in the liquid phase can more effectively protect the nanoparticles. An irreversible aggregation map was constructed as a function of the freezing rate and the cryoprotectant concentration, and shows both the favorable and unfavorable effects of cryoprotectants.

Mechanism of freeze-drying drug nanosuspensions

Drug nanoparticles prepared in a liquid medium are commonly freeze-dried for the preparation of an oral dosage in solid dosage form. The freezing rate is known to be a critical parameter for redispersible nanoformulations. However, there has been controversy as to whether a fast or slow freezing rate prevents irreversible aggregation. A systematic investigation is presented herein regarding the effect of both the molecular weight of the cryoprotectant and the freezing rate in order to elucidate the mechanism underlying irreversible aggregation. It was found that irreversible aggregation occurred during drying rather than freezing, although a proper freezing rate is critical. A more homogeneous distribution of the cryoprotectant and drug nanoparticles led to more redispersible powders. Thus, keeping the local concentration distribution of the nanoparticles and cryoprotectant fixed during the freezing step plays a critical role in how the freezing rate affects the redispersibility. The kinetic approach of excluding the tendency of ice crystal growth permitted an explanation of the controversial results. This study will facilitate an in-depth understanding of the aggregation process of nanoparticles or proteins during freeze-drying.

Large-area PVDF membranes with through-thickness porosity prepared by uni-directional freezing

AbstractAn ideal microporous membrane has uniformity through-thickness pores with low tortuosity. In this study, a novel uni-directional freezing method to manufacture poly(vinylidene fluoride) (PVDF) membranes with ideal pore structures is proposed. Crack-free large-area membranes can be produced by inducing the directional growth of cylindrical solvent crystals at a controlled freezing speed and removing them by freeze drying or solvent etching. These membranes are uniform and are regularly arrayed through-thickness pores and relatively strong mechanical properties (modulus=75 MPa and tensile strain to break=0.1). Filterability tests where membranes are produced via freeze drying reveal a fast average filtration rate compared to commercial membranes. In addition, Xray diffraction and infrared spectroscopy results confirmed that uni-directional freezing increased the beta phase content, possibly by inducing polymer chain alignment through directional solvent crystal growth. The obtained findings show that the uni-directional freezing method is a simple and effective process to control through-thickness pore structures.