Formulation and Process Optimization of Cinnarizine Fast-Release Tablets

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).

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.

Figure 1: Modes of melt agglomeration: (a) distribution and (b) immersion. (FIGURE IS COURTESY OF THE AUTHORS)

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.

Materials and methods

Materials. CNZ was supplied by Rakshit DPL (Bombay, India). Lactose monohydrates and PEG 6000 were procured from S.D. Fine Chemicals (Mumbai, India). All chemicals and solvents used in this study were of analytical reagent grade. Freshly distilled water was used throughout the work.

Fluidized-bed melt granulation. CNZ, PEG, and lactose monohydrate were granulated in a fluidized-bed dryer. The unit consisted of a conical container with a fine-mesh nylon gauze air distributor, stainless-steel support gauze, and a filter bag at the top of the unit. In the granulation experiments, various temperatures (56, 60, 64, and 68 °C) were used to melt the PEG. A temperature controller provided an accuracy of ±1 °C. The mean air speed was maintained at predetermined levels (350, 450, 550, and 650 m³/h). The 200-g formulations were co-melted and fluidized for predetermined periods (5, 10, 15, and 20 min). Because the granulation temperature exceeded the melting temperature of PEG, the granules were cooled and consolidated by fluidizing the granulate under ambient air for 30 s at the end of each granulation run. This experimental procedure ensured rapid crystallization of the PEG and is referred to as short isothermal crystallization time (ICT) (5).

Granule characterization. Differential scanning calorimetry (DSC) analysis. DSC scans of powdered samples from all of the ingredients individually and of the melt granules were recorded using a DSC- Shimadzu 60 instrument with TDA trend line software. All samples were weighed (8–10 mg) and heated at a scanning rate of 20 °C/min under dry airflow (100 mL/min) between 50 and 300 °C. Aluminum pans and lids were used for all samples.

Granule size and shape. A granule-size distribution study was performed with a vibrating sieve shaker (Kevin Engineering, Ahmedabad, India) (11). Granules' size, shape, and surface were characterized with a scanning electron microscope (SEM, Philips XL30 ESEM TMP, FEI, Hillsboro, OR).

Friability. A friability test was carried out with 10-g granules placed in a Roche friabilator (Campbell Electronics Mumbai, India) for 5 min at 25 rpm (11).

Drug content. Granules were dissolved in methanol. The drug content was determined with a UV spectrophotometer at 254 nm (Shimazdu-1601 UV–vis spectrophotometer, Shimadzu, Kyoto, Japan).

Ungranulated materials. The presence of powder materials that were not granulated may be attributed to insufficient binder concentration or fluidization. The materials were retained as ungranulated and weighted against total weight of materials.

Dissolution study. Dissolution studies of all samples were performed with USP XXIII apparatus type 2. Granules equivalent to 25 mg of CNZ were added to the dissolution medium (900 mL of distilled water at 37 ± 0.5 °C), which was stirred with a rotating paddle at 50 rpm. At suitable time intervals, 10-mL samples were withdrawn, filtered (0.22 μm), diluted, and analyzed at 254 nm with the UV spectrophotometer. An equal volume of fresh medium prewarmed at the same temperature was replaced in the dissolution medium after each sampling to maintain its constant volume throughout the test. Each test was performed in triplicate, and calculated mean values of cumulative drug release were used while plotting the release curves (13).

Figure 2: Differential scanning calorimetry spectra of granules prepared with (a) melt granulation, (b) cinnarizine, (c) lactose monohydrate, (d) poly(ethylene glycol) 6000. (FIGURE IS COURTESY OF THE AUTHORS)

Results and discussion

DSC analysis. DSC curves obtained for powdered CNZ, lactose monohydrate, PEG 6000, and granules prepared by melt granulation are shown in Figure 2. Pure powdered CNZ exhibited a melting endotherm at 125.54 °C. DSC scans of lactose monohydrate and PEG 6000 showed single sharp endotherms at 154.65 and 69.08 °C, respectively, due to melting of both compounds.

Table I: Experimental conditions used to study the effect of binder and process parameters.

DSC thermograms of granules of CNZ, lactose monohydrate, and PEG 6000 showed an absence of CNZ and the presence of sharp endothermic peaks because of the melting of PEG 6000 and lactose monohydrate. This complete absence of CNZ peak indicates that CNZ is present as amorphous or as a solid solution inside the PEG matrix.

Figure 3: Size distribution of granules prepared with various binder concentrations. (FIGURE IS COURTESY OF THE AUTHORS)

Effect of binder concentration. The various granulation batches prepared to study the effect of binder concentration are listed in Table I (batches M1–M3). Figure 3 shows the particle-size distributions of the granules prepared using various binder concentrations. Ungranulated fines decreased as the concentration of PEG increased from 10.0% to 20.0% (w/w). Particle-size distribution widened as the PEG content of the feed increased from 10.0% to 20.0% (w/w). When granulation was attempted with a PEG content of 25% (w/w), slurry was produced (i.e., the system was over-wetted and defluidized). In Figure 3, there is evidence of the emergence of overwetting in the granulation with a feed with PEG content of 20 % (w/w).

Figure 4: In vitro dissolution of granules prepared with various binder concentrations. (FIGURE IS COURTESY OF THE AUTHORS)

The in vitro dissolution rate of all prepared granulates increased compared with that of the drug alone. This increase is a result of the higher hydrophilic character of the systems due to the carriers and the slight reduction of CNZ crystallinity (see Figure 4). No significant in vitro dissolution differences were attested among the granules prepared using various concentrations of the binder.

Figure 5: Size distribution of granules prepared with binder of various particle sizes. (FIGURE IS COURTESY OF THE AUTHORS)

Effect of binder particle size. Various granulation batches prepared to study the effect of binder particle size on granule characteristics are listed in Table I (batches M4–M6). The size distribution of granules prepared with binders having various particle sizes is shown in Figure 5. These data indicate that particle-size distribution widened as the particle size of PEG increased from 195 to 642 μm. Granule size was directly proportional to the binder particle size (see Figure 6). Particles are easily agglomerated with the binder's larger particle size.

Figure 6: Scanning electron micrograph of granules prepared with poly(ethylene glycol) 6000 of particles size (a) 642 μm, (b) 343 μm, and 195 μm. (FIGURE IS COURTESY OF THE AUTHORS)

In vitro dissolution profiles of granules prepared using a binder of various particle sizes are shown in Figure 7. The in vitro dissolution rate of all prepared granulates improved compared with that of the drug alone because of the superior hydrophilic character of the systems. A slight increase in dissolution rate was observed with a decrease in the binder's average particle size from 642 to 195 μm.

Figure 7: In vitro dissolution of granules prepared with binder of various particle sizes. (FIGURE IS COURTESY OF THE AUTHORS)

Effect of granulation time. Table I lists the experimental conditions used to study the effect of granulation time (batches M7–M10), and Figure 9 shows a plot of cumulative mass fraction versus particle size with respect to granulation time (PEG 6000). The data indicate a considerable increase in particle size from the initial distribution to a granulation time of 5 min, with further granule growth occuring between 5 and 10 min. After 10 min, the particle-size distribution increased slightly (PEG content 15% w/w). It is interesting to note that the percentage of granules between 0.44 and 1.6 mm, the typical particle size range for pharmaceutical tablet pressing, was in excess of 50% for a granulation time of 10–20 min. These results are indicative of nucleation followed by the agglomeration process, whereby initial nuclei are formed and coalescence of particles takes place. However, further granule growth is limited to a relatively short time period. Because of the relative particle size of the binder and powder, the nucleation process is probably immersion nucleation, whereby the lactose powder adheres to and immerses into the molten PEG particles (14). Some previous studies on melt granulation indicate that nucleation and coalescence are the predominant growth regimes encountered.

Figure 8: Scanning electron microscopy (SEM) image of granules at (a) 10 min granulation time, 21 × magnification, (b) 10 min granulation time, 127 × magnification, (c) 20 min granulation time, 21 × magnification, (d) 20 min granulation time, 127 × magnification. (FIGURE IS COURTESY OF THE AUTHORS)

An SEM study (see Figure 8) showed that at 10 min of granulation, the mechanism of granule growth was nucleation, and at 20 min, nucleation was followed by agglomeration, whereby initial nuclei were formed and coalescence of particles took place.

Figure 9: Granule size distribution after various granulation times. (FIGURE IS COURTESY OF THE AUTHORS)

Effect of fluidizing air velocity. The data presented in Table I show the operating conditions used to investigate the influence of fluidizing air velocity (batches M11–M14). The variation in median size correlated with increased fluidizing air velocity. In all cases, the granule size was lower at a higher velocity. At the lowest fluidizing air velocity (350 m³/h), reduction in solids motion resulted in local overwetting, thus causing the defluidization of the bed. As the fluidized air velocity increased from 450 m³/h to 650 m³/h, mean granule size decreased, which may be attributed to the increase in the number of collisions at a faster velocity (see Figure 10).

Figure 10: Granule size distribution at various fluidized air velocities. (FIGURE IS COURTESY OF THE AUTHORS)

Effect of bed temperature. Table I lists the experimental conditions used to study the effect of bed temperature (batch M15–M18). At 60 °C, materials are completely fluidized and granules were produce with superior characteristics. When granulation was attempted at higher temperatures (64 and 68 °C), the bed defluidized and many lumps formed. The main cause for this occurrence is that these operating bed temperatures fall within the melting range of the binders, thereby inhibiting binder solidification to form granules. The authors' investigation into the influence of bed temperature using PEG 6000 clearly showed that the mean diameter of granules increased with increased bed temperature. The former observation can be explained by the hypothesis of Vander Scheur on the basis of the difference in binder solidification and heat transfer rate at increased bed temperature. For example, a higher bed temperature will induce a slower binder solidification rate, and the binder will remain molten for a longer period. This means the binder will have more time to promote more particle aggregation before it solidifies, thus leading to a faster growth rate with increased bed temperature (15).

Figure 11: Scanning electron microscopy (SEM) images of granules produced at (a) 60 °C and (b) 68 °C. (FIGURE IS COURTESY OF THE AUTHORS)

The granules formed at higher bed temperatures (e.g., 64 and 68 °C) and are more closely bound by a thicker and smoother binder layer (see Figure 11). At higher bed temperatures, the amount of lumps increased because of the binder's slow solidification rate (see Figure 12). Consolidation might have occurred in this case because the particles were allowed to move and pack closer as the binder remained molten for a longer period. The granules formed in this way are perhaps stronger because of their lower porosity. However, the faster binder solidification rate induced at a lower bed temperature might have encouraged a faster solid bridge formation, which could in turn lead to weaker bonding and thus produce a more friable granule. Such granules are more likely to break; therefore, the rate of solid bridge rupture might have increased. In contrast, the slower binder solidification rate induced at higher bed temperature might have caused the liquid bridge to rupture more easily than the solid bridge (16). However, the ruptured liquid bonds are still capable of causing further aggregation, which has probably produced granules with hardly any surface breakages.

Figure 12: Granule size distribution at various bed temperatures. (FIGURE IS COURTESY OF THE AUTHORS)

Conclusion

The authors studied various formulations and experimental conditions of fluidized hot-melt granulation for preparing granules of cinnarazine with PEG 6000 as a melt binder. The concentration of PEG 6000 had no significant effect on in vitro drug release profile, but particle size of PEG 6000 slightly changed the in vitro drug-release profile. Both variables influenced the granules' physical properties such as ungranulated fines and size. Increased granulation time led to an increased granule size. Increasing the fluidization velocity resulted in a decreasing mean granule size, because of the increase in the number of collision between particles. At bed temperatures higher than the melting point of the binder, granules had greater strength. However, defluidization of the powder bed was a difficulty at higher temperatures and also produced lumps. Granule size also increased at higher temperatures. At lower bed temperatures, granules with lower strength were produced that could not withstand the fluidization air pressure and broke into very small granules or fines. Therefore, fluidized hot-melt granulation has been proven to be a viable means of producing granules of cinnarazine with PEG 6000 as a melt binder, without the use of solvents or water.

Rakesh P. Patel, PhD,* is an assistant professor and head of the pharmaceutics and pharmaceutical technology department at S. K. Patel College of Pharmaceutical Education and Research, Ganpat Vidyanagr, Kherva, India 382711. Ajay Suthar is a postgraduate at the department of pharmaceutics of S.K. Patel College of Pharmaceutical Education and Research, raka_77us@yahoo.com

*To whom all correspondence should be addressed.

Submitted: Nov. 3, 2008. Accepted: Dec. 11, 2008.

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