Formulation and Process Optimization of Cinnarizine Fast-Release Tablets

The authors prepared granules containing cinnarizine using polyethylene glycol 6000 as a melting binder and lactose monohydrate as hydrophilic filler. The effects of binder concentration and size were studied.
Aug 02, 2009
Volume 33, Issue 8

Fluidized hot-melt granulation (FHMG) is a nonambient process that results in the phase transition of a solid-state binder in situ. These binders are used to prepare pharmaceutical granules having a suitable size and compression profile for processing with fluid-bed granulation. Melt granulation facilitates the manufacture of various dosage forms and formulations such as immediate and sustained-release pellets, granules, and tablets (1).

Figure 1: Modes of melt agglomeration: (a) distribution and (b) immersion. (FIGURE IS COURTESY OF THE AUTHORS)
The elementary mechanisms of agglomeration are distribution and immersion (see Figure 1). In agglomeration by distribution, molten-binding liquid is distributed on the surfaces of primary particles, and agglomerates are formed as a result of coalescence between the wetted nuclei (2). Agglomeration by immersion occurs when nuclei are formed by immersion of the primary particles onto the surface of a droplet of molten-binding liquid. The mechanism of melt agglomeration is similar to that of wet agglomeration.

Abberger et al. and Schaefer et al. showed that granule growth depends on the ratio of binder droplet size to powder particle size (3, 4). In their studies, a low ratio led to nucleation, which resulted in coalescence and further granule growth. Kidokoro et al. showed the viscosity of the binder melt affects the increase in granule size during FHMG and that the properties of the binder material influenced the physical properties of tablets pressed from the fluidized hot-melted granules (5).

The melt granulation process has several advantages over conventional methods. For example, melt granulation does not involve solvents, thereby eliminating the problems associated with in-process hydrolysis and water removal by means of heating when using aqueous granulation fluids. Melt granulation is a simple and rapid process that can be performed in one step, which is in contrast to conventional wet granulation whereby transfer from the granulator to the drying equipment is usually necessary and may result in transfer losses, equipment contamination, increased processing and operator time, and large amounts of dust (6). The absence of extraneous liquid may lead to a more favorable binder:substrate ratio as well as a higher granule density and reduced porosity. That said, some granule porosity is required to allow water to penetrate during disintegration. A significant advantage of melt granulation is that the judicious choice of the granulation excipient may enable a formulator to manipulate the drug's dissolution rate from the corresponding dosage form (7, 8).

Cinnarizine (CNZ) is a poorly water-soluble Class II drug that has a low bioavailability in its crystalline form. For poorly water-soluble drugs, the rate of oral absorption is often controlled by the dissolution rate in the gastrointestinal tract. Therefore, dissolution is the rate-limiting step in the absorption of poorly water-soluble drugs. CNZ is an antihistaminic drug that is mainly used for motion sickness. Conventional tablets showed that 50% of CNZ is precipitated in the intestinal compartment because of lower solubility at higher pH (0.002 mg/mL in phosphate buffer pH 7.2) (9, 10).

In the present study, the authors attempted to:

  • Formulate granules of CNZ by melt granulation using a small-scale commercial fluidized-bed granulator with hydrophilic meltable binder such as poly(ethylene glycol) (PEG) 4000 and PEG 6000 to improve the dissolution characteristics of poorly water-soluble CNZ
  • Study the effect of formulation and experimental conditions of the fluidized hot-melt granulation process.

lorem ipsum