475290 Controlling amorphization versus crystallization of carbamazepine nanoparticles using a supercritical-assisted spray drying process

Monday, November 14, 2016
Grand Ballroom B (Hilton San Francisco Union Square)
Luis Padrela, Barry Long and Kevin M. Ryan, University of Limerick, Limerick, Ireland

Spray drying is now regarded as one of the most commonly used technologies in the pharmaceutical industry for API (Active Pharmaceutical Ingredient) particle production in the micron-size range1. It is a method of producing dry powders from a solution or a suspension by rapidly evaporating solvent with a hot air stream. This is one of the preferred technologies for material processing and scale-up in the pharmaceutical and food industries because it is a fast, continuous, and a one-step process. However, the solid-state nature of the spray-dried materials is often amorphous due to rapid solidification and is restricted to the micron size scale range. Although amorphous materials provide huge improvements in the APIs apparent solubility, a major limitation of these materials is that the drug is thermodynamically unstable and tends to recrystallize during storage (depending on the stability provided by the polymer matrix in the solid dispersion) where the outcome might be a crystalline form with a much lower solubility.

Pharmaceutical crystalline materials provide a higher potential for enhanced solid state stability of poorly soluble APIs compared to amorphous materials, although providing a poorer solubilities and dissolution rates. Interestingly, producing poorly soluble APIs as nanocrystals provides considerable improvements in their solubility, dissolution rate as well as solid-state stability. One of the most successful top-down methods to obtain APIs nanocrystals or solid nanocrystalline dispersions with the desired size distribution consists of wet milling APIs down to a nano size range, adding excipients to these nanosuspensions to inhibit crystal growth due to Ostwald ripening and spray drying them later on2. However, milling limits the control of the API crystal habit and other surface properties, can take long times to achieve the required size, can introduce impurities from abrasion of the milling media, and can lead to thermal/mechanical degradation of temperature-sensitive materials.

In this work a supercritical CO2-assisted spray drying technology has been used to produce and control the solid-state form carbamazepine (e.g. amorphous, crystalline) in a nano-sized range. This process involves contacting the API solution with supercritical CO2 in the nozzle and immediately spraying it through the nozzle exit for solvent extraction at atmospheric pressure3. By restricting the high pressure exclusively to where it is indispensable, it is possible to control the precipitation of the API before the nozzle (anti-solvent nucleation/crystallization) or after the nozzle (atomization/spray drying) while providing processing flexibility. This also facilitates the adaptation of this technology onto existing spray drying equipments.

Solutions of CBZ (carbamazepine) dissolved in methanol ([CBZ] = 50mg/ml) with or without selected additives (e.g. ethyl cellulose, sodium stearate, maltitol, Kollidon VA64) were spray dried using supercritical CO2. In this process the carbamazepine solutions are fed to the nozzle exit, while immediately and continuously feeding the solutions or suspensions through the nozzle to obtain the final powders. Depending on the type of spray drying mechanism being used (atomization or antisolvent-assisted atomization) by changing process variables (e.g. pressure, temperature, supercritical antisolvent/solvent ratio) has provided control on the size and solid-state outcome (e.g. amorphous, crystalline) of the carbamazepine nanoparticles. The inclusion of small amounts of selected additives (0.1-10% w/w) in the carbamazepine-methanol solutions has provided an additional step to controlling the formation of nanoparticles in the amorphous form or favoring the crystallization of a particular polymorph.

1. Vehring R. Pharm. Res. 25 (2008) 999-1022.

  1. Paredes et al. Drug Dev. Ind. Pharm. (2016), DOI: 10.3109/03639045.2016.1151036
  2. Padrela et al. J. Supercrit. Fluids 86 (2014) 129-136.

This work has been supported by Science Foundation Ireland, Grant number: 12/RC/2275.

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See more of this Session: Poster Session: Pharmaceutical
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