A novel bottom–up process to produce drug nanocrystals: Controlled crystallization during freeze-drying

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Abstract

To improve the dissolution behavior of lipophilic drugs, a novel bottom–up process based upon freeze drying which allows for the production of nanocrystalline particles was developed: “controlled crystallization during freeze drying”. This novel process could strongly increase the dissolution behavior of fenofibrate. For example at a drug load of 30% w/w, 80% of the drug dissolved within 10 min from tablets prepared from the controlled crystallized dispersions, while from tablets prepared from the physical mixture only 50% was dissolved after 120 min. Furthermore it was found that faster freezing or using a solution with a lower water/tertiary butyl alcohol (TBA) ratio resulted in faster dissolution, indicating that the crystalline dispersions contained smaller crystals. Crystallization of the drug could occur during freezing or during drying. When crystallization occurs during freezing, faster freezing or using solutions with a lower water/TBA ratio results in the formation of more nuclei and consequently smaller crystals. When crystallization occurs during drying, faster freezing or using solutions with a higher water/TBA ratio results in the formation of smaller solvent crystals and therefore smaller interstitial spaces which contain the freeze-concentrated fraction. Since crystallization occurs in the freeze-concentrated fraction and the size of the crystals are limited to the size of the interstitial spaces, smaller crystals are formed in these situations.

Introduction

Many new drugs can be considered to be class II drugs according to the Biopharmaceutics Classification System [1]. These drugs are poorly water soluble, but once they are dissolved, they are easily absorbed over the gastro-intestinal membrane [2], [3]. Therefore the bioavailability after oral administration can be improved by enhancement of the dissolution rate [4].

One of the approaches to enhance the dissolution rate is the application of amorphous solid dispersions [5], [6]. Such solid dispersions are composed of a hydrophilic matrix in which a poorly soluble drug is dispersed [7]. Application of these fully amorphous solid dispersions is theoretically an ideal method to improve the dissolution rate, because the saturation concentration as well as the surface area available for dissolution increases [6]. However, molecules in the amorphous state are thermodynamically unstable relative to the crystalline state. Therefore uncontrolled crystallization of the drug or matrix material could occur during processing or storage of the amorphous solid dispersion [8], [9], [10], [11]. This crystallization of the drug is unwanted, because it may affect the dissolution behavior. In many cases crystallization of the carrier can be prevented by choosing a carrier with a high glass transition temperature (Tg), but for a given drug the Tg cannot be changed. When a drug has a low Tg the risk of uncontrolled crystallization is high, in particular when the drug is incorporated in the solid dispersion as clusters [12]. An example of such a drug is fenofibrate, which has a Tg of − 21.3 °C [13].

The undesired crystallization can be prevented by using a system which is already in its most stable state: the crystalline state. However, the drug crystals have to be sufficiently small (i.e. nanoscale) to obtain a large surface area as well as an increased saturation concentration (Kelvin law) and therefore high dissolution rate [14], [15]. Processes to produce nanocrystals can be categorized as top–down and bottom–up processes. Typical top–down processes are high pressure homogenization [16] and wet ball milling [17]. Disadvantages of these processes are the use of surfactants, the long processing times, the difficulty in achieving a uniform size distribution, low yields, high energy input and possible contamination from the grinding media [18], [19], [20]. Bottom–up processes are basically precipitation processes. A disadvantage of most currently applied bottom–up processes is that the final drug crystal size cannot be controlled adequately [20], [21].

To overcome these disadvantages, we propose a novel bottom–up process to produce drug nanocrystals. This process is based on a technique used to produce amorphous solid dispersions developed within our laboratory [22]. These amorphous solid dispersions were prepared by freeze drying a solution of drug and sugar in a mixture of water and tertiary butyl alcohol (TBA). In contrast to this previous process, we now present a new process that produces fully crystalline solid dispersions. By taking a drug with a low Tg (fenofibrate), a carrier (mannitol) that easily crystallizes during freeze-drying, and freeze-drying at a relatively high shelf temperature, we envisage that crystallization can occur either during freezing or during drying. The freeze-drying conditions (freezing rate and composition of the solution to be freeze dried) were manipulated to evaluate whether crystalline dispersions could be obtained and whether the particle size and therefore the dissolution rate can be controlled.

Section snippets

Materials

Fenofibrate and TBA were obtained from Sigma-Aldrich Chemie B.V. Zwijndrecht, the Netherlands. Mannitol was provided by Roquette, France. Demineralized water was used in all experiments.

Preparation of the crystalline solid dispersion

Two separate solutions were prepared: one of mannitol in water and the other of fenofibrate in TBA (for compositions see Table 1). After heating the solutions to about 60 °C, the aqueous solution was mixed with the TBA solution in 10 mL glass injection vials. In all cases (except for the drip and freeze

Drug load

The degree of crystallinity of the dispersions (prepared from solutions at a water/TBA ratio of 6/4; vials frozen in liquid nitrogen, as described in Table 2) was determined by XRPD and DSC. Crystalline mannitol can have three anhydrous polymorphic forms (α-, β-, and δ-mannitol). The melting points (166.5 °C, 166 °C, and 155 °C respectively) and melting enthalpies (52.1 kJ/mol, 53.5 kJ/mol, and 53.7 kJ/mol respectively) of these polymorphic forms differ only slightly [23]. Therefore XRPD was

Discussion and conclusions

In this study we present a novel process to prepare drug nanocrystals. These nanocrystals were prepared by freeze-drying a solution of a drug and a sugar in a mixture of water and TBA. A drug with a low Tg (fenofibrate) and a carrier (mannitol) which easily crystallizes were used. In addition, freeze drying was performed at a relatively high temperature. With this novel process, highly crystalline dispersions could be prepared which showed a strongly improved dissolution behavior compared to

Acknowledgements

This research was performed within the framework of project T5-105 of the Dutch Top Institute Pharma. The authors would like to thank P. Pfaffenbach (Solvay Infra Bad Hönningen GmbH, Hannover, Germany) for his assistance on XRPD analysis.

References (26)

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