Formulation Development of Taste-Masked Rapidly Dissolving Films of Cetirizine Hydrochloride

Rapidly dissolving dosage forms have acquired great importance in the pharmaceutical industry because of their unique properties (1, 2). Rapidly dissolving dosage forms are also called quick-dissolving delivery systems; quick-disintegrating, orally disintegrating, mouth dissolve dosage forms; or melt-in-mouth dosage forms (1, 3, 4). In less than one minute, these dosage forms disintegrate or dissolve in the salivary fluids of the oral cavity, releasing the drug and inactive ingredients. Most of the drug is swallowed with the saliva where subsequent absorption takes place in the gastrointestinal tract (3, 4).

Rapidly dissolving dosage forms offer advantages such as disintegration without water, rapid onset of action, ease of transportability, ease of handling, pleasant taste, and improved patient compliance. These dosage forms are most widely available as rapidly dissolving tablets (3, 4). Lyophilized wafers, thin strips, and films are newer types of rapidly dissolving dosage forms that can be manufactured using technologies such as freeze drying, vacuum drying, the incorporation of superdisintegrants, spray drying, and molding methods (1, 2).

Rapidly dissolving films (RDF) have been popular in the market predominantly for breath-freshening products. However, RDFs have recently been introduced in the United States and Europe for therapeutic products as well (2, 5–8). A film or strip comprises a water soluble polymer that causes the film or strip to dissolve when placed on the tongue. The first oral strip was developed by Pfizer (New York) as a mouth freshening product ("Listerine" pocket packs). "Chloraseptic Relief Strips" (distributed by Prestige Brands, Irvington, NY), for the treatment of sore throat pain, was the first therapeutic oral thin-film product that contained benzocaine (6, 8).

RDFs are prepared using fast disintegrating polymers that possess good film-forming properties e.g., hydroxypropyl methylcellulose [HPMC], pullulan, and hydroxypropylcellulose [HPC]) (9). HPMC E LV is a low-viscosity white to off-white modified cellulose powder that is a good solubilizer and possesses swelling characteristics. Various grades of HPMC E LV (i.e., E3, E5, and E15) were selected for this study. Solvent casting, semisolid casting, hot melt extrusion, solid dispersion extrusion, and rolling are processes used to manufacture RDFs. Solvent casting is the most common and traditional method (2). RDFs are typically evaluated for thickness, mechanical properties such as tensile strength and elasticity, in vitro and in vivo disintegration, and in vitro dissolution (10, 11).

Cetirizine hydrochloride (CTZ) is an orally active and selective H1-receptor antagonist used to treat seasonal allergic rhinitis, perennial allergic rhinitis, and chronic urticaria. CTZ is a white, crystalline water-soluble drug with a bitter taste (12, 13). Because of sore throat conditions, patients may experience difficulty in swallowing a tablet. Therefore, an RDF would serve as an ideal dosage form for these patients.

The authors formulated and developed an RDF of CTZ. The study of a CTZ RDF also involved applying taste-masking techniques to formulate a dosage form with acceptable taste. HPMC with various viscosity grades (i.e., E3, E5 and E15 LV) was selected as the film-forming polymer, and solvent casting was selected as a method of manufacture.

Materials and methods

Materials. Cetirizine hydrochloride was received as a gift sample from Troikaa Pharmaceuticals (Ahmedabad, India). HPMC E3 LV, HPMC E5 LV, and HPMC E15 LV were received as gift samples from Colorcon Asia (Goa, India). Sucralose was obtained as a gift sample from Alkem Lab (Ankleshwar, India). Citric acid anhydrous was purchased from Central Drug House (New Delhi, India). Menthol and polyethylene glycol (PEG) 400 were purchased from S.D. Fine Chem (Mumbai, India). Aspartame was purchased from Hi-Media Lab (Mumbai). Passion fruit flavor and lemon flavor were received as gift samples from Pentagon Trading Company (Ahmedabad, India). All other chemicals were of analytical grade and were used without further purification. Double distilled water was used for the study.

Table I : In vitro disintegration time of preliminary batches without drug.

Preparation of the RDFs. RDFs of CTZ with various grades of HPMC E LV were prepared using a solvent casting method (2). An aqueous solution of HPMC was prepared in distilled water, and CTZ was added to the aqueous polymeric solution. This step was followed by the addition of menthol, which had been dissolved in ethyl alcohol (95%), and plasticizers such as PEG 400 or glycerol. Sweeteners aspartame and sucralose, citric acid, and flavor were also added. The solution was cast on a 9-cm diameter glass Petri dish and dried at room temperature for 24 h. The film was carefully removed from the Petri dish, checked for imperfections, and cut to the required size to deliver the equivalent dose (2 × 2 cm² ) per strip. The samples were stored in a dessicator at 30–35% relative humidity until further analysis. Film samples with air bubbles, cuts, or imperfections were excluded from the study. The formulation batches are described in Table I and Table II.

Table II : Selection of sweeteners for taste masking of rapidly dissolving films.

Mechanical properties of the RDFs. The RDFs were evaluated for mechanical properties using a universal testing machine (model LR 100 K Lloyd Instruments, Ametek, Leicester, England) with load cell 100 N. RDFs of size 10 × 2.5 cm² and free of physical imperfections were held between two clamps held 5-cm apart. The 10 × 2.5 cm² dimension was selected because it is the minimum size required for sample testing on the machine. The RDFs were pulled by the clamp at a rate of 50 mm/min. Mechanical properties of the film were measured in triplicate for each batch. Tensile strength, elastic modulus, and percent elongation were calculated for the RDFs as described below.

Tensile strength is the maximum stress applied to a point at which the film specimen breaks and can be computed from the applied force at rupture as a mean of three measurements and the cross-sectional area of the fractured film as calculated using the equation:

Elastic modulus is the ratio of applied stress and corresponding strain (force in N) in the region of approximately linear proportion of elastic deformation on the load displacement profile and calculated using the equation:

Percentage elongation was calculated using the following equation:

Fourier transfer infrared spectroscopy. The identification of CTZ in RDF was conducted with a fourier transfer infrared spectrophotometer (Jasco, FTIR model 6100, Japan).

In vitro disintegration studies. Disintegration time provided an indication about the disintegration characteristics and dissolution characteristics of the film. For this study, the film as per the dimensions (2 × 2 cm² ) required for dose delivery was placed on a stainless steel wire mesh containing 10 mL of distilled water. The time required for the film to break was noted as in vitro disintegration time (2, 10).

In vivo disintegration studies. The in vivo disintegration time was measured in six human volunteers. An RDF was placed on the tongues of the volunteers and time required for disintegration in the mouth was noted.

In vitro dissolution studies.In vitro dissolution studies were conducted using three dissolution media: distilled water (500 mL), simulated gastric fluid (900 mL), and simulated saliva (500 mL) (11). The studies were performed using USP dissolution apparatus XXIV (Electrolab, Mumbai, India) at 37 × 0.5 °C and at 50 rpm using specified dissolution media. Each film with dimension (2 × 2 cm² ) was placed on a stainless steel wire mesh with sieve opening 700 μm. The film sample placed on the sieve was submerged into dissolution media. Samples were withdrawn at 2, 5, 10, 15, 30, 60, and 120 min time intervals, filtered through 0.45-μm Whatman filter paper, and analyzed spectrophotometrically at 231 nm (UV 2450 Shimadzu Scientific Instrument, Kyoto, Japan). To maintain the volume, an equal volume of fresh dissolution medium maintained at same temperature was added after withdrawing samples. The absorbance values were converted to concentration using a standard calibration curve previously obtained by experiment. The dissolution testing studies were performed in triplicate for all the batches.

Taste evaluation. Taste acceptability was measured by a taste panel with 10 mg drug and subsequently 10-mg film sample held in the mouth for 5–10 s, then spat out, and the bitterness level was recorded (6, 14). Volunteers were asked to gargle with distilled water between the drug and sample administration. The following scale was used:

• + = very bitter

• ++ = moderate to bitter

• +++ = slightly bitter

• ++++ = tasteless or taste-masked.

Results and discussion

Fourier transfer infrared spectroscopy. FTIR spectra of the pure drug showed significant bands at 3427, 2839, 2587, 1741, and 1600 cm^–1, which indicates the presence of hydroxyl, ether stretching, tertiary amine salt, carbonyl groups, and phenyl nucleus skeletal stretching, respectively, and confirms the purity of the drug.

Preliminary trials were undertaken for designing the RDF wherein the effects of various grades of HPMC namely E3, E5, and E15 LV on the characteristics of the films were assessed. All three grades were varied in a concentration range of 1–4% w/v (see Table I). The initial trials were taken to evaluate the suitability of various grades of HPMC for the formation of RDF without addition of the drug.

In vitro disintegration time studies as shown in Table I suggested that films prepared with all three grades of HPMC had in vitro disintegration time below 30 s and were therefore acceptable.

Films prepared at 1% w/v concentration with all three grades were very thin, brittle, and easily broken. Films with 2–4% w/v concentration for all three grades were clear, transparent, and easily separated. Therefore, further batches containing the drug were formulated using 2–4%w/v of HPMC E grades.

RDFs containing 200 mg HPMC E5 LV formulated with CTZ resulted in highly brittle films compared with films containing 400 mg HPMC E5 LV, which separated easily. Thus, films containing 400 mg HPMC E5 LV were further evaluated for various parameters. The reason for the brittle film formation in the presence of the drug using 200 mg HPMC E5 LV might be insufficient in the sample required for film formation. The in vitro disintegration time of batches containing 400 mg HPMC E5 LV was acceptable (45 s). Trials were also conducted with the same formulation in presence (containing 0.7 mg menthol per dose) and absence of menthol as a cooling agent and plasticizer. The in vitro dissolution study of the above batches indicated total drug release in 10 and 30 min with and without menthol respectively. Thus, the in vitro dissolution was found to be slightly extended.

The RDFs containing 200 mg HPMC E15 LV formulated with CTZ resulted in films with good quality and acceptable in vitro disintegration time (45 s). Films with 400 mg HPMC E15 LV resulted in higher in vitro disintegration time (95 s), which might be a result of delayed disintegration time with the higher viscosity grade of HPMC E LV.

Incorporating CTZ with 200 mg of HPMC E3 LV resulted in the formation of very brittle and thin films. CTZ incorporated with 400 mg of HPMC E3 LV resulted in slightly brittle films. Thus, it is necessary to add placticizer to improve the characteristics of these films. Various preliminary formulations (E1 to E8) using 400 mg of HPMC E3 LV were prepared with glycerol and menthol as plasticizers to evaluate film separation. None of these batches exhibited good film separation. Batches were prepared with glycerol and PEG 400. The batch with PEG 400 at a plasticizer:polymer ratio of 0.2:1 exhibited better elasticity than the batch prepared with glycerol. Therefore, film separation could be improved in the presence of plasticizer.

The in vitro disintegration time of batch E9 containing 400 mg of HPMC E3 LV, CTZ, and PEG 400 was 25 s. The comparative drug release of batch E9 in various dissolution media indicated 85% drug release in 2 min in distilled water, 81% drug release in 2 min in 0.1 N HCl, and 78% drug release in 2 min in simulated saliva.

Therefore, the viscosity grades of HPMC E LV affected the mechanical properties, disintegration, and dissolution characteristics of the RDFs. Higher viscosities of HPMC E LV grade exhibited increased in vitro disintegration and dissolution times. Although batches containing 400 mg HPMC E5 LV and 200 mg HPMC E15 LV in presence of drug had an in vitro disintegration time of 45 s, the in vitro dissolution time was 30 min and 45 min in distilled water, respectively. Batch E9 had 85% drug release in 2 min in distilled water. RDFs containing CTZ prepared with HPMC E3 LV also possessed satisfactory mechanical properties, in vitro disintegration, and in vitro dissolution time and were used for further optimization. Therefore, further trials were carried out using HPMC E3 LV as the polymer for RDF formulation development.

Taste masking of CTZ films. Because CTZ is bitter in taste, taste masking the films was essential to improve patient acceptability. To improve the taste of the films, flavors and sweeteners were incorporated in the film formulation.

The addition of menthol (5% w/w of drug and polymer amount) and aspartame (10% w/w of drug and polymer amount) at various plasticizer ratios did not mask the taste of the film. Thus, further trial batches S1 to S4 were taken with the sweetener sucralose, which also did not result in taste masking of the films. Additional trials were conducted using combinations of aspartame and sucralose.

Table II shows that films of batch S4 had a satisfactory invitro disintegration time of 50 s. In vivo disintegration time of the film of batch S4 was 20 s. This batch possessed a good taste masking property but also had a bitter aftertaste. Thus, further formulation modifications were carried out by adding flavoring agents such as lemon and passion fruit flavors and sour ingredients such as citric acid.

Table III : Selection of flavors.

Table III indicates that the subsequent addition of citric acid and passion fruit flavor (batches T1 and T3) resulted in completely taste-masked films. The in vitro disintegration time was 50 s and the in vivo disintegration time of batch T3 was 20 s. The addition of lemon flavor (batches T2 and T4) resulted in highly acidic taste of the film, which was unacceptable. Batch T3 showed good elasticity and taste masking properties. Figure 1 indicates the comparative in vitro dissolution profile of batch T3 in different dissolution media. Figure 1 shows that in 2 min batch T3 showed 100% drug release in distilled water, 95% in 0.1 N HCl, and 80% in simulated saliva.

Figure 1: Comparative in-vitro dissolution profile of batch T3. (FIGURE IS COURTESY OF THE AUTHORS.)

Study of mechanical properties. A suitable RDF requires moderate tensile strength, good percentage elongation, and low elastic modulus. Table IV shows the comparative mechanical properties of various formulations prepared during the study. RDFs containing 2% and 4% HPMC E3 LV without drug (i.e., batches 2E and 4E) showed extremely high tensile strength, poor percent elongation, and very high elastic modulus. The same formulation in the presence of drug and plasticizer (i.e., batch E9) demonstrated lower tensile strength compared with batch 2E and 4E. The percent elongation values increased and elastic modulus values decreased. The taste-masked batches S4 and T3 had acceptable mechanical properties. The tensile strength was in a moderate range (4–9 N/m² ). The percent elongation (21–28) and elastic modulus (35–165) were also satisfactory. These changes in the mechanical properties can be attributed to the presence of plasticizer in batches E9, S4, and T3. Batch T3 showed the most acceptable mechanical properties along with complete taste masking, which might be attributed to the presence of suitable plasticizers and flavors. The stability study of the optimized batch T3 was carried out at 25 ?C for a one-year period. The batch was found be acceptable visually, mechanically, with a slight increase in the in vitro and in vivo disintegration time of 55 s and 22 s, respectively.

Table IV : Comparative mechanical properties.

Conclusion

RDFs containing taste-masked CTZ showed acceptable properties such as tensile strength, elasticity, percentage elongation, in vitro disintegration, and in vitro dissolution characteristics. The RDFs were transparent, without any air entrapment. The drug-release profiles indicated that it could be used for the oral delivery of CTZ in chronic and acute urticaria as well as perennial rhinitis. Taste masking could be achieved using suitable sweeteners, flavors, and sour ingredients. The various grades of HPMC E LV highly affected the in vitro disintegration time and in vitro dissolution profiles. HPMC E3 LV was the most suitable grade for the manufacture of RDF containing CTZ.

Renuka Mishra is a lecturer in the department of pharmaceutical technology, and Avani Amin, PhD,* is principal and I/C director, both at the Institute of Pharmacy, Nirma University of Science and Technology, Sarkhej-Gandhinagar Highway, Ahmedabad, Gujarat, India, tel. 91 02717 241900 to 04, fax 91 02717 241916, avanifamin@yahoo.com

*To whom all correspondence should be addressed.

Submitted: May 1, 2008. Accepted: May 9, 2008.

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