http://informahealthcare.com/phd ISSN: 1083-7450 (print), 1097-9867 (electronic) Pharm Dev Technol, Early Online: 1–8 ! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/10837450.2014.1003657
RESEARCH ARTICLE
Application of freeze-drying technology in manufacturing orally disintegrating films Pharmaceutical Development and Technology Downloaded from informahealthcare.com by RMIT University on 03/14/15 For personal use only.
Kai Bin Liew1 and Michael Ayodele Odeniyi2 1
Department of Pharmaceutical Technology, UCSI University, Kuala Lumpur, Malaysia and 2Department of Pharmaceutics & Industrial Pharmacy, Faculty of Pharmacy, University of Ibadan, Ibadan, Nigeria Abstract
Keywords
Freeze drying technology has not been maximized and reported in manufacturing orally disintegrating films. The aim of this study was to explore the freeze drying technology in the formulation of sildenafil orally disintegrating films and compare the physical properties with heat-dried orally disintegrating film. Central composite design was used to investigate the effects of three factors, namely concentration of carbopol, wheat starch and polyethylene glycol 400 on the tensile strength and disintegration time of the film. Heat-dried films had higher tensile strength than films prepared using freeze-dried method. For folding endurance, freeze-dried films showed improved endurance than heat-dried films. Moreover, films prepared using freeze-dried methods were thicker and had faster disintegration time. Formulations with higher amount of carbopol and starch showed higher tensile strength and thickness whereas formulations with higher PEG 400 content showed better flexibility. Scanning electron microscopy showed that the freeze-dried films had more porous structure compared to the heat-dried film as a result of the release of water molecule from the frozen structure when it was subjected to freeze drying process. The sildenafil film was palatable. The dissolution profiles of freeze-dried and heat-dried films were similar to ViagraÕ with f2 of 51.04 and 65.98, respectively.
Freeze-drying, oral disintegrating films, sildenafil citrate
Introduction Over the past few decades, there has been an increased interest for innovative drug delivery systems to improve safety, efficacy and patient compliance, thereby increasing the product patent life cycle1,2. In view of these needs, academic researchers and pharmaceutical industries have been partnering together to discover and develop several fast disintegrating drug delivery systems such as orally disintegrating tablet (ODT) and orally disintegrating film (ODF). Statistics have shown that four out of five patients prefer orally disintegrating dosage forms over conventional solid oral dosages. These factors, coupled with convenience and compliance advantages will continue to pave the way for ODT and ODF drug product growth3. Orally dissolving films serve as an alternative to orally disintegrating tablet to provide quick release of an active pharmaceutical ingredient (API) when placed on the tongue. When wet by saliva, the film rapidly hydrates and disintegrates to release the drug. Advantages of ODFs over the conventional solid dosage forms are improved portability, ease of administration, accurate dosing, cost-effectiveness and improved patient
Address for correspondence: Dr Michael Ayodele Odeniyi, B. Pharm; Ph.D., Department of Pharmaceutics & Industrial Pharmacy, Faculty of Pharmacy, University of Ibadan, Ibadan, Nigeria. E-mail: [email protected]
History Received 15 November 2014 Revised 26 December 2014 Accepted 27 December 2014 Published online 19 January 2015
compliance4. Moreover, ODF has advantage over ODT to eliminate completely the fear of choking because it appears in thin film form, rather than tablet shape form5,6. The formulation of fast disintegrating oral film involves the intricate application of aesthetic and performance characteristics like fast disintegrating, taste-masking, physical appearance and mouth feel. The common adjuvants are film forming polymers, thickening agent, plasticizer, suitable solvent and organoleptic improving agents7. The manufacturing methods of ODF are solvent casting, semisolid casting, hot-melt extrusion (HME), solid-dispersion extrusion and rolling. However, solvent casting and hot melt extrusion are reported as the most common methods due to the simplicity8–12. In solvent casting method, the water-soluble ingredients are dissolved in a suitable solvent to form a viscous solution. The drug and other smaller quantity ingredients are dissolved in another portion of smaller volume solvent and combined with the bulk drug later on. The entrapped air is removed by vacuum and the resulting solution is cast as a film and allowed to dry. Oven or heat is commonly applied due to faster removal of solvent and forming of film. The ODF is then cut into pieces to the desired size. The drying temperature plays an important role13. In the HME process, the drug and other excipients are mixed in a dry state. The mixture is then subjected to heating process to melt the mixture and the molten mass is then extruded out of the hot-melt extruder. The advantage of this process is the complete elimination of the solvent. The films are
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K. B. Liew & M. A. Odeniyi
Pharm Dev Technol, Early Online: 1–8
allowed to cool and are cut to the desired size14. The major limitation for both methods is their unsuitability for drug candidates which are heat-sensitive. Freeze drying (lyophilization) is a process in which solvent is removed from a frozen drug solution or a suspension containing structure-forming excipients. This technology was used to manufacture ODT in 1970 and patented as Zydis Technology. Zydis ODT is very light and has highly porous structures that allow rapid disintegration, within seconds. The entire freeze drying process is done at non-elevated temperatures to eliminate adverse thermal effects that may affect drug stability during processing. Another property of the freeze-drying process is that it may result in a glassy amorphous structure of excipients as well as the drug substance, leading to the enhanced dissolution rate14,15. However, this technology has not been maximized and reported in formulating ODF. The objective of this study is to investigate the potential of an alternative method for solvent removal in solvent casting method. Instead of using heat to remove the solvent, this study explores the freeze-drying technology. The ODF prepared using heat-drying and freeze-drying methods was compared and characterized afterward.
Experimental design A central composite design for three factors and two responses was used for the oral disintegrating films (Design Expert 9.0.3, Stat-Ease Inc., Minneapolis, MN). The factors considered were concentration of Carbopol (0.5–1.5), concentration of wheat starch (0.5–1.5) and concentration of PEG 400 (0.5–1.5). Central composite design (CCD) is a well established statistical technique for determining the key factors from a large number of medium components by a relatively small number of experiments. Heat drying (HD) method The weighing boats were dried in an oven at 60 C for 6 h. The film was removed from the weighing boat and stored in a desiccator. Freeze drying (FD) method The weighing boats were stored in a freezer at 20 C for 2 h to freeze the sample. The frozen samples with the weighing boat were then transferred into the freeze dryer to freeze dry under vacuum suction for 6 h. The film was removed from the weighing boat and stored in a desiccator.
Materials and methods Materials
Physical characterization
Sildenafil citrate was a gift from Ind-Swift Laboratory Limited (Chandigarh, India). Hydroxypropyl methylcellulose (HPMC) and polyethylene glycol 400 (PEG) were purchased from Sigma Chemical Co. (St. Louis, MO). Wheat starch was extracted from wheat grains purchased from Bodija market, Ibadan, Nigeria using established procedures16,17. Sucralose and pineapple flavor were purchased from Nutrisweet & Food Specialities Sdn. Bhd. (Malaysia).
Uniformity of thickness
Preparation of ODF Hydroxypropyl methylcellulose (HPMC) and wheat starch were sieved through a No. 40 mesh screen (diameter 0.5 mm), respectively. HPMC was dissolved in 30 g of distilled water and heated at 60 C with the aid of a magnetic stirrer for mixing purpose. Wheat starch and polyethylene glycol (PEG) were then mixed added into the viscous polymeric solution and homogenized at 2000 rpm for 30 min (IKA Works, Inc., Wilmington, NC). The sweetener, flavoring agent and sildenafil citrate were separately dissolved in 10 g of distilled water and added to the mixture prepared earlier. The weight was adjusted to 50 g with distilled water and homogenization was continued for another 30 min. A 1 g sample of the final mixture was weighed and transferred into 20 20 8 mm flat bottom polypropylene weighing boat each. The formulations are presented in Table 1.
The thickness of each ODF formulation (20 20 mm) was measured using a micrometre (Mitutoyo, Japan) at the centre point. Six samples of each ODF formulation were measured. Tensile strength measurement The tensile strength of the ODF was measured using a texture analyzer (TX-XT2 texture analyzer, North America). The samples of ODF at dimension of 20 20 mm were held vertically between two clamps at 1 cm apart. The ODF was pulled by the clamp at a rate of 100 mm/min and contact force of 0.05 N. The tensile strength was defined as the maximum load force to break the ODF and calculated by dividing the applied load at rupture with the cross-sectional area of the film15. For each formulation, six samples were measured. Tensile strenght ¼
Load at failure Strip thickness Strip width
ð1Þ
Folding endurance determination The ODF (20 20 mm) was repeatedly folded at the same place. The total number of foldings made before the film cracked was
Table 1. Various formulations of ODF base by heat-dried and freeze-dried methods. Formulation (g/50 mL) Ingredient Carbopol Wheat starch PEG 400 Ingredient Carbopol Wheat starch PEG 400
1
2
3
4
5
6
7
8
9
10
1.84 1.00 1.00
0.16 1.00 1.00
1.00 0.16 1.00
1.50 0.50 1.50
0.50 0.50 0.50
1.00 1.84 1.00
1.50 1.50 1.50
1.00 1.00 1.00
1.00 1.00 0.16
1.00 1.00 1.84
11
12
13
14
15
16
17
18
19
20
1.00 1.00 1.00
1.00 1.00 1.00
0.50 0.50 1.84
1.00 1.00 1.00
0.50 1.50 0.50
0.50 1.50 1.50
1.50 0.50 0.50
1.00 1.00 1.00
1.00 1.00 1.00
1.50 1.50 0.50
Freeze dried orally disintegrating films
DOI: 10.3109/10837450.2014.1003657
denoted as folding endurance value. The ODF was examined for cracks over the area of the bend under a strong light. For each formulation, six samples were examined. In vitro disintegration time study The in vitro disintegration time of the ODF formulations (20 20 mm) was determined using a disintegration tester (Pharmatest, Germany) with distilled water at 37.0 ± 0.5 C. The disintegration time was defined as the time taken for ODF to completely disintegrate with no solid residue remaining on the screen. A total of six ODF samples were run for each formulation.
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Selection of optimum formulation An optimum base in terms of tensile strength and disintegration time was chosen for further testing. The optimum base was incorporated with model drug which was sildenafil citrate, sweetener and flavor. The final formulation is presented in Table 2. The preparation method was the same for heat-dried and freeze-dried methods as described above. Physical characterization and uniformity of drug content The final formulation was characterized physically using the characterization mentioned above and the drug content was determined using a HPLC-UV system. The HPLC system was comprised of a Shimadzu (VP series, Kyoto, Japan) pump (LC20AT vp) with solvent cabinet, a degasser (DGU-20A3), a column oven (CTO-10S VP), an auto-injector (SIL-20A HT vp), UV/VIS detector (SPD-20A vp) and a computer software (LC-Solution VP). The separation was carried out using a Synchronize C-18 column (150 4.6 mm ID, 5 mm) (Thermo Scientific, Waltham, MA). The flow rate was set at 1.5 mL/min, column temperature was set at 30 C and detection wavelength of 240 nm was used. Sample of 25 mL was injected onto the column. Ammonium acetate buffer solution (0.2 M) was mixed with acetonitrile at 1:1 ratio at pH 7.40. The mobile phase was stirred using a magnetic stirrer for 15 min. The pH of the mobile phase was checked using a pH meter. The mobile phase was then filtered through Whatman nylon membrane filters 0.45 mm using a filtration set. The filtered mixture was degassed using a sonicator for 15 min. A piece of ODF film (20 20 mm) was dissolved in mobile phase by sonication. After appropriate dilution, 25 mL of the sample was injected into the HPLC and the amount of drug was determined. Six ODF (20 20 mm) of each formulation were examined. Scanning electronic microscopy (SEM) SEM images were obtained using the scanning electron microscope (VE-7300, Keyence). The heat-dried and freeze-dried Sildenafil films were mounted on a metal stub with double-sided adhesive tapes. The sample was sputtered with a thin layer of gold to improve the electrical conductivity prior to imaging.
3
In vitro drug dissolution study The dissolution studies were carried out on the optimum heatdried and freeze-dried ODF formulation and the original product (ViagraÕ ). Drug dissolution study was carried out in 900 mL of phosphate buffer (pH 4.5 ± 0.1) at 37.0 ± 0.5 C, using USP basket method at a stirring speed of 100 rpm. At preset time intervals of 5, 10, 15, 20, 30, 45, 60, 90 and 120 min, 1 mL of samples were withdrawn and immediately replaced with an equal volume of fresh dissolution medium. The samples were filtered through 0.45 mm membrane filter and the amount of drug released was determined using a validated HPLC-UV method. Similarities between the dissolution profiles were assessed by a pair-wise model independent procedure, similarity factor (f2)18,19: 8" 9 #0:5 < = 1 f2 ¼ 50Log 1 þ Pn¼i 100 ð2Þ : ; n n¼1 ðRt Tt Þ2 where n is the number of pull points, wt is an optional weight factor, Rt is the reference profile at time point t and Tt is the test profile at the same time point; the value of f2 should be between 50 and 100. A f2 value of 100 suggests that the test and reference profiles are identical and dissimilarity between release profiles increases as the value becomes smaller. In situ disintegration time and palatability studies A total of 12 healthy adult volunteers with age between 22 and 55 years old participated in this study after providing written informed consent. Prior to the study, the volunteers were briefed on the nature, purpose, duration and risk of the study. The study protocol was approved by the University Human Research Ethics Committee (JePEM USM). Prior to the study, the volunteers were required to gargle their mouth with 200 mL of distilled water. One ODF was placed on the tongue of the volunteer. The volunteers were requested to give the score based on a five-points scale to evaluate three parameters namely taste, after taste and acceptance as stated in Table 3. The volunteers were told to spit out the test sample, followed by Table 3. Parameters and score in palatability study. Taste Very bitter Bitter Slightly bitter Slightly sweet Very sweet
Aftertaste
Acceptance
Score
Very bitter Bitter Slightly bitter Slightly sweet Very sweet
Very poor Poor Acceptable Good Very good
1 2 3 4 5
Table 2. Final formulation of ODF by heat-dried and freeze-dried methods.
Ingredient Sildenafil citrate Carbopol Wheat starch PEG 400 Sucralose Green apple flavor
Weight (g/50 mL of casting solution) 1.00 0.50 1.50 1.50 1.00 1.00
Figure 1. The photograph of sildenafil (A) heat-dried and (B) freeze-dried method.
ODF
prepared
using
Tensile strength (N/cm2) Folding endurance (times) Thickness (mm) Disintegration time (s)
Parameter
Tensile strength (N/cm2) Folding endurance (times) Thickness (mm) Disintegration time (s)
Parameter
Tensile strength (N/cm2) Folding endurance (times) Thickness (mm) Disintegration time (s)
Parameter
3.96 ± 1.22
799.83 ± 15.65
620.67 ± 1.75 143.50 ± 8.19
6.14 ± 1.03
780.17 ± 14.91
570.83 ± 2.14 161.67 ± 6.77
FD
610.17 ± 1.72 211.00 ± 7.92
561.00 ± 1.26 231.67 ± 8.45
F15
899.00 ± 15.62
877.83 ± 17.68
HD
6.88 ± 1.09
9.48 ± 1.19
FD
628.00 ± 2.45 271.17 ± 8.23
577.67 ± 1.37 290.33 ± 8.31
HD
861.83 ± 18.61
840.67 ± 19.20
F8
9.38 ± 1.71
FD
11.93 ± 1.86
HD
F1
F9
554.33 ± 1.75 174.50 ± 10.78
2.75 ± 1.28
FD
604.67 ± 1.51 148.00 ± 8.88
928.33 ± 15.65
4.74 ± 1.28
FD
604.33 ± 2.50 186.67 ± 7.42
752.67 ± 18.99
5.19 ± 0.48
FD
598.33 ± 3.44 124.67 ± 8.21
826.17 ± 11.89
F16
908.00 ± 16.66
7.10 ± 1.15
HD
555.67 ± 1.50 205.67 ± 7.00
732.67 ± 18.90
7.72 ± 0.71
HD
550.33 ± 1.86 143.50 ± 7.66
805.50 ± 11.29
4.98 ± 1.33
HD
F2
551.50 ± 2.17 221.33 ± 8.64
600.83 ± 1.94 201.50 ± 9.18
781.00 ± 11.63
6.34 ± 0.65
FD
625.83 ± 1.72 242.50 ± 9.35
977.17 ± 34.50
7.36 ± 1.06
FD
596.33 ± 2.16 138.67 ± 10.54
F17
759.00 ± 12.90
8.48 ± 0.93
HD
575.50 ± 1.52 262.50 ± 8.31
3.68 ± 0.53
FD
831.83 ± 7.52
F10
957.50 ± 35.46
10.27 ± 1.05
HD
547.33 ± 1.97 156.00 ± 7.82
811.00 ± 8.05
5.88 ± 0.68
HD
F3
561.50 ± 2.07 234.50 ± 9.14
612.33 ± 2.50 206.67 ± 12.96
896.50 ± 12.13
6.71 ± 1.22
FD
611.17 ± 1.83 212.17 ± 9.15
897.67 ± 10.17
6.67 ± 1.23
FD
621.33 ± 1.86 233.17 ± 9.83
F18
876.33 ± 10.97
9.11 ± 1.28
HD
562.00 ± 1.90 230.83 ± 9.75
7.48 ± 1.12
FD
951.00 ± 24.34
F11
878.33 ± 11.22
9.14 ± 1.20
HD
571.83 ± 2.14 252.50 ± 8.69
930.33 ± 24.78
9.91 ± 1.24
HD
F4
Formulation
3.37 ± 0.92
HD
561.17 ± 2.04 229.00 ± 9.12
875.50 ± 8.17
9.28 ± 0.91
HD
561.83 ± 1.47 232.17 ± 8.13
F5
1.62 ± 0.57
FD
6.88 ± 1.05
FD
610.17 ± 1.47 208.33 ± 9.54
894.83 ± 10.32
F19
610.50 ± 1.64 213.00 ± 8.67
898.17 ± 10.68
6.74 ± 1.21
FD
590.33 ± 2.42 109.33 ± 8.04
777.50 ± 18.73
F12
876.33 ± 13.81
9.12 ± 1.19
HD
539.17 ± 3.76 128.50 ± 9.69
757.00 ± 18.11
Table 4. The results of physical characterization of ODF prepared using heat-dried and freeze-dried methods. Mean ± SD, n ¼ 6.
590.50 ± 1.76 304.33 ± 7.06
9.52 ± 1.32
FD
639.33 ± 1.75 284.17 ± 7.17
813.17 ± 13.80
9.28 ± 0.89
FD
594.50 ± 2.43 112.67 ± 9.85
910.67 ± 23.00
2.49 ± 1.22
FD
535.83 ± 1.72 251.83 ± 7.88
842.67 ± 8.43
F20
793.83 ± 11.30
11.84 ± 0.89
HD
544.67 ± 1.63 136.17 ± 9.26
F6
F13
890.67 ± 22.72
4.44 ± 0.89
HD
586.67 ± 2.16 272.00 ± 7.72
822.17 ± 8.98
10.36 ± 1.22
HD
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560.67 ± 2.16 228.50 ± 8.17
10.00 ± 1.24
FD
610.17 ± 2.32 212.00 ± 9.21
896.33 ± 14.56
6.70 ± 1.23
FD
642.67 ± 2.16 295.00 ± 6.16
960.17 ± 24.59
F14
876.00 ± 12.70
9.18 ± 1.50
HD
593.83 ± 2.14 314.00 ± 6.23
940.50 ± 26.73
12.87 ± 1.28
HD
F7
4 K. B. Liew & M. A. Odeniyi Pharm Dev Technol, Early Online: 1–8
Freeze dried orally disintegrating films
DOI: 10.3109/10837450.2014.1003657
5
Table 5. Process variables used in Central Composite Design for oral dissolving films with the correspondent fit model and prediction equation for each parameter tested.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Fit model Predict equationa
Factor 1 A: Carbopol
Factor 2 B: Wheat starch
Factor 3 C: PEG 400
Response 1 Tensile strength (N/cm2)
Response 2 Disintegration time (s)
3.68 0.32 2.00 3.00 1.00 2.00 3.00 2.00 2.00 2.00 2.00 2.00 1.00 2.00 1.00 1.00 3.00 2.00 2.00 3.00
2.00 2.00 0.32 1.00 1.00 3.68 3.00 2.00 2.00 2.00 2.00 2.00 1.00 2.00 3.00 3.00 1.00 2.00 2.00 3.00
2.00 2.00 2.00 3.00 1.00 2.00 3.00 2.00 0.32 3.68 2.00 2.00 3.00 2.00 1.00 3.00 1.00 2.00 2.00 1.00
11.93 4.98 5.88 9.91 3.37 10.36 12.87 9.48 7.72 10.27 9.14 9.12 4.44 9.18 6.14 7.10 8.48 9.11 9.28 11.84 Linear ¼+220.48 + 54.06 A + 30.10 B + 11.49 C
290.33 143.5 156 252.5 128.5 272 314 231.67 205.67 262.5 230.83 232.17 136.17 228.5 161.67 174.5 221.33 234.5 229 304.33 Quadratic ¼+9.23 + 2.47A + 1.41 B + 0.64 C + 0.11 AB + 0.054 AC 0.064 BC 0.37 A2 0.49 B2 0.18 C2 0.9607 25.283
R2 Adeq. Precision
0.9151 26.519
a
A: Carbopol; B: Wheat starch; C: PEG 400.
Figure 2. Response surface plot for the effect of polymer concentration on the film tensile strength for oral disintegrating films.
14 12 10
hardness (kg)
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Formulations
8 6 4 2
3.00
3.00 2.50
2.50 2.00
2.00 1.50
B: Wheat starch
1.50 1.00
A: Carbopol
1.00
rinsing their mouths with 200 mL of distilled water. There was a wash out period for 2 h before the second formulation was administered on the same group of volunteers.
difference. For stability study, post hoc Dunnet’s test (two sided) was performed, comparing with zero month data. A statistically significant difference was considered at p50.05.
Statistical analysis
Results
The results were expressed as mean ± standard deviation (SD). Statistical Procedure for Social Science (SPSS), Ver 16.0 (SPSS Inc., Chicago, IL) was used for statistical analysis. The results obtained from physical evaluations were analyzed statistically using one-way analysis of variance (ANOVA). Post hoc TukeyHSD test was carried out when there was a statistically significant
The images of freeze-dried and heat-dried film are presented in Figure 1. Heat-dried film was transparent but freeze-dried film was white in color. The results of tensile strength, folding endurance, thickness and in vitro disintegration time are presented in Table 4. The experimental design employed in this study provided a predictable equation for each of the parameters
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K. B. Liew & M. A. Odeniyi
Pharm Dev Technol, Early Online: 1–8
Figure 3. Response surface plot for the effect of polymer concentration on the disintegration time for oral disintegration films.
350 300
dt (s)
250 200 150 100
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3.00 2.50 2.00 3.00
2.50
2.00
1.50 1.50
A: Carbopol
1.00 1.00
B: Wheat starch
examined, according to a refined model which can be found in Table 5. Generally, it was noted that film prepared using heatdried method has higher tensile strength than film prepared using freeze-dried method for the same formulation and the difference was statistically significant (p50.05). For folding endurance film prepared using freeze-dried method showed improved endurance than the same formulation prepared using heat-dried method and the difference was found statistically significant (p50.05). Moreover, film prepared using freeze-dried method was thicker and had faster disintegration time than the same formulation prepared using heat-dried method. Formulations with higher amount of carbopol and starch showed higher tensile strength and thickness whereas formulations with higher PEG 400 content showed better flexibility. The fitted model for the hardness of the ODT is linear and shows that the interaction terms are insignificant. However, a second order quadratic model best described the disintegration profile. The refined model was used for drawing contour plots, as shown in Figures 2 and 3, respectively. The results are very clear in distinguishing formulation f16 as the optimum in terms of ODT strength and disintegration time, and were used for the final formulation. Formulation f16 has the highest tensile strength among the formulations with in vitro disintegration time less than 180 s. The physical characterization and drug content of final formulation prepared using heat-dried and freeze-dried methods are presented in Table 6. The final formulation after incorporation of model drug, sweetener and flavor showed variation in physical characterization parameters. The tensile strength and folding endurance reduced while the disintegration time and thickness increased compared to the base. The drug content was within the close range of 98–102%. The SEM micrographs of the films are shown in Figure 4. The freeze-dried film showed more porous structure compared to the heat-dried film. The porosity formed as a result of the release of water molecule from the frozen structure when it was subjected to freeze drying process. As a result, the disintegration time of the freeze-dried film was shorter than the heat-dried film. It also explained the weaker tensile strength of the freeze-dried film. The drug dissolution profiles of heat-dried and freeze-dried ODF and ViagraÕ are presented in Figure 5. The three products released 80% of the drug content within 45 min.
Table 6. The results of physical characterization of final formulation of ODF prepared using heat-dried and freeze-dried methods. Mean ± SD, n ¼ 6. Formulation Parameter Tensile strength (N/cm2) Folding endurance (times) Thickness (mm) In vitro disintegration time (s) In situ disintegration time (s) Drug content (%) Palatability study (score) a. Taste b. Aftertaste c. Acceptance
HD
FD
6.67 ± 0.12 897.67 ± 5.92 585.67 ± 4.41 183.50 ± 4.04 176.50 ± 3.56 99.50 ± 0.72
4.41 ± 0.12 919.50 ± 3.94 634.83 ± 3.43 165.67 ± 4.03 156.00 ± 2.90 99.12 ± 0.75
4.38 ± 0.52 4.13 ± 0.64 4.75 ± 0.46
4.50 ± 0.53 4.25 ± 0.71 4.63 ± 0.52
Discussion The demand for orally disintegrating dosage forms has markedly increased because it provides a means of providing a patient friendly, economical and yet effective drug delivery system20. Oral disintegrating films are ultra-thin and flexible strips of postage stamp size films, with an active pharmaceutical ingredient or combination of active pharmaceutical ingredients, which disintegrate within a minute when in contact with water or saliva. They offer the advantages of large surface area, rapid onset of action, accuracy of dosage, taken without water and could be designed for specific groups of people to solve non-compliance issues5. Formulation 16 was chosen for the final formulation as it was the optimum base in terms of tensile strength and disintegration time. The preparation method was the same for heat-dried and freeze-dried methods with the sildenafil citrate, flavor and disintegrant incorporated. PEG 400 was incorporated as plasticizer to increase film flexibility as well as improve ease of film removal from the mould. There was no significant difference (p40.05) in the result of content uniformity (Table 5). The sildenafil citrate content in the formulations using the two different methods of formulation ranged from 99.12 ± 0.75% to 99.50 ± 0.72% of the theoretical
Freeze dried orally disintegrating films
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DOI: 10.3109/10837450.2014.1003657
7
Figure 4. SEM micrograph of (A) heat-dried sildenafil film and (B) freeze-dried sildenafil film.
Figure 5. Dissolution profiles of heat-dried, freeze-dried sildenafil films and Viagra in 900 mL phosphate buffer (pH 4.5) using USP basket method with stirring speed at 100 rpm (mean ± sd, n ¼ 6).
concentration. This shows the suitability of both methods in producing formulations of uniform drug content. The ODF prepared using the heat drying method was significantly (p50.05) stronger than those prepared by freeze drying. Values of tensile strength were 6.67 ± 0.12 and 4.41 ± 0.12 N/cm2 for the heat-dried and freeze-dried formulations, respectively. Freeze-dried products have generally been found to be fluffy and weaker than comparable heat-dried products. These could be due to the freezing and drying technique employed. This prevents the formation of solid bridges characteristic of heat drying21. The tensile strength of the ODF was further assessed using film flexibility determination. The folding endurance results for the films from the two techniques employed showed the FD formulation to be more significantly flexible than the HD samples. However, ODF from both formulations did not show signs of crack after been folded 180 at the same place up to 800 times and the formulations could be defined as flexible and would be stable under pressure encountered during manufacture, transportation and handling22. The in vitro disintegration time was 183.50 ± 4.04 s for HD and 165.67 ± 4.03 s for the FD ODTs. The faster disintegration observed in the FD formulations could be attributed to greater water uptake due to the porous nature of the film structure. The in situ disintegration time for HD films was 176.50 ± 3.56 s
and 156.00 ± 2.90 s for FD ODFs. The results are similar to those obtained in vitro and suggest a correlation in in vitro/in situ disintegration properties of the films. The drug dissolution profiles of HD and FD ODF formulations and ViagraÕ are presented in Figure 3. The dissolution profiles for the three formulations were very similar with 80.0% of sildenafil citrate been released within 45 min in all the formulations. The similarity factor (f2) for HD and FD final formulations were 65.98 and 51.04, respectively. From the palatability evaluation, the final formulations of both HD and FD were found sweet in taste and after taste and acceptable. The freeze-dried formulations were very light and gave a highly porous structure which provided rapid disintegration. Also, the freeze drying process is accomplished at non-elevated temperatures and thus eliminating adverse thermal effects which may affect drug stability during processing in contrast to heat drying. Further, freeze drying may produce a glassy amorphous structure of excipients and the drug substance, hence improving the dissolution rate14.
Conclusion The results obtained from this work showed that: Oral disintegrating films of sildenafil citrate with good mechanical and release properties were prepared using freeze-drying and heat-dried technique. Freeze-dried films generally showed lower tensile strength, but better folding endurance and disintegration time compared to heat-dried film. Increase in carbopol and starch concentrations in the film formulations increased tensile strength and disintegration time. The films were found to have good palatability and masked the taste of the active ingredient in the formulation.
Declaration of interest The authors report no conflicts of interest The authors are grateful to TWAS, The World Academy of Sciences and Universiti Sains Malaysia for the TWAS-USM Postdoctoral Fellowship granted MAO.
References 1. Panda BP, Dey NS, Rao MEB. Development of innovative orally fast disintegrating film dosage forms: a review. Int J Pharm Sci Nanotech 2012;5:1666–1674.
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2. Heinemann RJB, Carvalho RA, Favaro-Trindade CS. Orally disintegrating film (ODF) for delivery of probiotics in the oral cavity — development of a novel product for oral health. Innov Food Sci Emerg 2013;19:227–232. 3. Technology catalysts International Corporation. Available from: http://technology-catalysts.com/pdf/ODT_PressRelease-0106.pdf [last accessed 12 Feb 2014]. 4. Mishra R, Amin A. Manufacturing techniques of orally dissolving films. Pharma Tech 2011;35:70–73. 5. Liew KB, Yvonne TFT, Peh KK. Characterization of oral disintegrating film containing Donepezil for Alzheimer disease. AAPS PharmSciTech 2012;13:134–142. 6. Liew KB, Peh KK, Yvonne TFT. Orally disintegrating dosage forms: breakthrough solutions for non-compliance. IJPPS 2013;5:4–8. 7. Habib W, Khankari RK, Hontz J. Fast-dissolve drug delivery systems. Crit Rev Ther Drug Carrier Sys 2000;17:61–72. 8. Borsadia S, O’Halloran D, Osborne JL. Quick-dissolving films—a novel approach to drug delivery. Drug Deliv Technol 2003;3:63–66. 9. Mishra R, Amin A. Quick API delivery. Pharm Technol Eur 2007; 19:35–39. 10. Arya A, Chandra A, Sharma V, Pathak K. Fast dissolving oral films: an innovative drug delivery system and dosage form. Int J Chem Tech Res 2010;2:578–583. 11. Gole DJ, Wilkinson PK, Davies JD, Levinson RS. Pharmaceutical and other dosage forms. 1997; US Patent 5648093. 12. Yang RK, Fuisz RC, Myers GL, Fuisz GM. Thin film with non-self aggregating uniform heterogeneity and drug delivery systems made therefrom. 2002; US Patent Application 20080226695.
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13. Fu YR, Yang SC, Jeong SH, et al. Orally fast disintegrating tablets: developments, technologies, taste-masking and clinical studies. Crit Rev Ther Drug 2004;21:433–475. 14. Kathpalia H, Sule B, Gupte A. Development and evaluation of orally disintegrating film of tramadol hydrochloride. AJBPS 2013;3: 27–32. 15. Mishra R, Amin A. Manufacturing techniques of orally dissolving films. J Pharm Sci 2011;35:70–73. 16. Odeniyi MA, Ayorinde JO. Material and rheological properties of yam starch/polymer blend hydrogels. Int J Pharmacol Pharm Technol 2012;1:23–28. 17. Riley CK, Adebayo SA. A comparative investigation of the packing and flow properties of sweet potato (Ipomea batatas) starches and their potential uses in solid dosage formulations. Starch-Starke 2010; 62:285–293. 18. Adeleye AO, Odeniyi MA, Jaiyeoba KT. Evaluation of cissus gum as binder in a paracetamol tablet formulation. Farmacia 2011;59: 85–96. 19. Costa P, Manuel J. Modeling and comparison of dissolution profiles. Eur J Pharm Sci 2001;13:123–133. 20. Gauri S, Kumar G. Fast dissolving drug delivery and its technologies. Pharma Innov 2012;1:32–37. 21. Iqbal T, Fitzpatrick JJ. Effect of storage conditions on the wall friction characteristics of three food powders. J Food Eng 2006;72: 273–280. 22. Cilurzo F, Cupone IE, Minghetti P, et al. Fast dissolving films made of maltodextrins. Eur J Pharm Biopharm 2008;70: 895–900.
RESEARCH ARTICLE
Application of freeze-drying technology in manufacturing orally disintegrating films Pharmaceutical Development and Technology Downloaded from informahealthcare.com by RMIT University on 03/14/15 For personal use only.
Kai Bin Liew1 and Michael Ayodele Odeniyi2 1
Department of Pharmaceutical Technology, UCSI University, Kuala Lumpur, Malaysia and 2Department of Pharmaceutics & Industrial Pharmacy, Faculty of Pharmacy, University of Ibadan, Ibadan, Nigeria Abstract
Keywords
Freeze drying technology has not been maximized and reported in manufacturing orally disintegrating films. The aim of this study was to explore the freeze drying technology in the formulation of sildenafil orally disintegrating films and compare the physical properties with heat-dried orally disintegrating film. Central composite design was used to investigate the effects of three factors, namely concentration of carbopol, wheat starch and polyethylene glycol 400 on the tensile strength and disintegration time of the film. Heat-dried films had higher tensile strength than films prepared using freeze-dried method. For folding endurance, freeze-dried films showed improved endurance than heat-dried films. Moreover, films prepared using freeze-dried methods were thicker and had faster disintegration time. Formulations with higher amount of carbopol and starch showed higher tensile strength and thickness whereas formulations with higher PEG 400 content showed better flexibility. Scanning electron microscopy showed that the freeze-dried films had more porous structure compared to the heat-dried film as a result of the release of water molecule from the frozen structure when it was subjected to freeze drying process. The sildenafil film was palatable. The dissolution profiles of freeze-dried and heat-dried films were similar to ViagraÕ with f2 of 51.04 and 65.98, respectively.
Freeze-drying, oral disintegrating films, sildenafil citrate
Introduction Over the past few decades, there has been an increased interest for innovative drug delivery systems to improve safety, efficacy and patient compliance, thereby increasing the product patent life cycle1,2. In view of these needs, academic researchers and pharmaceutical industries have been partnering together to discover and develop several fast disintegrating drug delivery systems such as orally disintegrating tablet (ODT) and orally disintegrating film (ODF). Statistics have shown that four out of five patients prefer orally disintegrating dosage forms over conventional solid oral dosages. These factors, coupled with convenience and compliance advantages will continue to pave the way for ODT and ODF drug product growth3. Orally dissolving films serve as an alternative to orally disintegrating tablet to provide quick release of an active pharmaceutical ingredient (API) when placed on the tongue. When wet by saliva, the film rapidly hydrates and disintegrates to release the drug. Advantages of ODFs over the conventional solid dosage forms are improved portability, ease of administration, accurate dosing, cost-effectiveness and improved patient
Address for correspondence: Dr Michael Ayodele Odeniyi, B. Pharm; Ph.D., Department of Pharmaceutics & Industrial Pharmacy, Faculty of Pharmacy, University of Ibadan, Ibadan, Nigeria. E-mail: [email protected]
History Received 15 November 2014 Revised 26 December 2014 Accepted 27 December 2014 Published online 19 January 2015
compliance4. Moreover, ODF has advantage over ODT to eliminate completely the fear of choking because it appears in thin film form, rather than tablet shape form5,6. The formulation of fast disintegrating oral film involves the intricate application of aesthetic and performance characteristics like fast disintegrating, taste-masking, physical appearance and mouth feel. The common adjuvants are film forming polymers, thickening agent, plasticizer, suitable solvent and organoleptic improving agents7. The manufacturing methods of ODF are solvent casting, semisolid casting, hot-melt extrusion (HME), solid-dispersion extrusion and rolling. However, solvent casting and hot melt extrusion are reported as the most common methods due to the simplicity8–12. In solvent casting method, the water-soluble ingredients are dissolved in a suitable solvent to form a viscous solution. The drug and other smaller quantity ingredients are dissolved in another portion of smaller volume solvent and combined with the bulk drug later on. The entrapped air is removed by vacuum and the resulting solution is cast as a film and allowed to dry. Oven or heat is commonly applied due to faster removal of solvent and forming of film. The ODF is then cut into pieces to the desired size. The drying temperature plays an important role13. In the HME process, the drug and other excipients are mixed in a dry state. The mixture is then subjected to heating process to melt the mixture and the molten mass is then extruded out of the hot-melt extruder. The advantage of this process is the complete elimination of the solvent. The films are
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K. B. Liew & M. A. Odeniyi
Pharm Dev Technol, Early Online: 1–8
allowed to cool and are cut to the desired size14. The major limitation for both methods is their unsuitability for drug candidates which are heat-sensitive. Freeze drying (lyophilization) is a process in which solvent is removed from a frozen drug solution or a suspension containing structure-forming excipients. This technology was used to manufacture ODT in 1970 and patented as Zydis Technology. Zydis ODT is very light and has highly porous structures that allow rapid disintegration, within seconds. The entire freeze drying process is done at non-elevated temperatures to eliminate adverse thermal effects that may affect drug stability during processing. Another property of the freeze-drying process is that it may result in a glassy amorphous structure of excipients as well as the drug substance, leading to the enhanced dissolution rate14,15. However, this technology has not been maximized and reported in formulating ODF. The objective of this study is to investigate the potential of an alternative method for solvent removal in solvent casting method. Instead of using heat to remove the solvent, this study explores the freeze-drying technology. The ODF prepared using heat-drying and freeze-drying methods was compared and characterized afterward.
Experimental design A central composite design for three factors and two responses was used for the oral disintegrating films (Design Expert 9.0.3, Stat-Ease Inc., Minneapolis, MN). The factors considered were concentration of Carbopol (0.5–1.5), concentration of wheat starch (0.5–1.5) and concentration of PEG 400 (0.5–1.5). Central composite design (CCD) is a well established statistical technique for determining the key factors from a large number of medium components by a relatively small number of experiments. Heat drying (HD) method The weighing boats were dried in an oven at 60 C for 6 h. The film was removed from the weighing boat and stored in a desiccator. Freeze drying (FD) method The weighing boats were stored in a freezer at 20 C for 2 h to freeze the sample. The frozen samples with the weighing boat were then transferred into the freeze dryer to freeze dry under vacuum suction for 6 h. The film was removed from the weighing boat and stored in a desiccator.
Materials and methods Materials
Physical characterization
Sildenafil citrate was a gift from Ind-Swift Laboratory Limited (Chandigarh, India). Hydroxypropyl methylcellulose (HPMC) and polyethylene glycol 400 (PEG) were purchased from Sigma Chemical Co. (St. Louis, MO). Wheat starch was extracted from wheat grains purchased from Bodija market, Ibadan, Nigeria using established procedures16,17. Sucralose and pineapple flavor were purchased from Nutrisweet & Food Specialities Sdn. Bhd. (Malaysia).
Uniformity of thickness
Preparation of ODF Hydroxypropyl methylcellulose (HPMC) and wheat starch were sieved through a No. 40 mesh screen (diameter 0.5 mm), respectively. HPMC was dissolved in 30 g of distilled water and heated at 60 C with the aid of a magnetic stirrer for mixing purpose. Wheat starch and polyethylene glycol (PEG) were then mixed added into the viscous polymeric solution and homogenized at 2000 rpm for 30 min (IKA Works, Inc., Wilmington, NC). The sweetener, flavoring agent and sildenafil citrate were separately dissolved in 10 g of distilled water and added to the mixture prepared earlier. The weight was adjusted to 50 g with distilled water and homogenization was continued for another 30 min. A 1 g sample of the final mixture was weighed and transferred into 20 20 8 mm flat bottom polypropylene weighing boat each. The formulations are presented in Table 1.
The thickness of each ODF formulation (20 20 mm) was measured using a micrometre (Mitutoyo, Japan) at the centre point. Six samples of each ODF formulation were measured. Tensile strength measurement The tensile strength of the ODF was measured using a texture analyzer (TX-XT2 texture analyzer, North America). The samples of ODF at dimension of 20 20 mm were held vertically between two clamps at 1 cm apart. The ODF was pulled by the clamp at a rate of 100 mm/min and contact force of 0.05 N. The tensile strength was defined as the maximum load force to break the ODF and calculated by dividing the applied load at rupture with the cross-sectional area of the film15. For each formulation, six samples were measured. Tensile strenght ¼
Load at failure Strip thickness Strip width
ð1Þ
Folding endurance determination The ODF (20 20 mm) was repeatedly folded at the same place. The total number of foldings made before the film cracked was
Table 1. Various formulations of ODF base by heat-dried and freeze-dried methods. Formulation (g/50 mL) Ingredient Carbopol Wheat starch PEG 400 Ingredient Carbopol Wheat starch PEG 400
1
2
3
4
5
6
7
8
9
10
1.84 1.00 1.00
0.16 1.00 1.00
1.00 0.16 1.00
1.50 0.50 1.50
0.50 0.50 0.50
1.00 1.84 1.00
1.50 1.50 1.50
1.00 1.00 1.00
1.00 1.00 0.16
1.00 1.00 1.84
11
12
13
14
15
16
17
18
19
20
1.00 1.00 1.00
1.00 1.00 1.00
0.50 0.50 1.84
1.00 1.00 1.00
0.50 1.50 0.50
0.50 1.50 1.50
1.50 0.50 0.50
1.00 1.00 1.00
1.00 1.00 1.00
1.50 1.50 0.50
Freeze dried orally disintegrating films
DOI: 10.3109/10837450.2014.1003657
denoted as folding endurance value. The ODF was examined for cracks over the area of the bend under a strong light. For each formulation, six samples were examined. In vitro disintegration time study The in vitro disintegration time of the ODF formulations (20 20 mm) was determined using a disintegration tester (Pharmatest, Germany) with distilled water at 37.0 ± 0.5 C. The disintegration time was defined as the time taken for ODF to completely disintegrate with no solid residue remaining on the screen. A total of six ODF samples were run for each formulation.
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Selection of optimum formulation An optimum base in terms of tensile strength and disintegration time was chosen for further testing. The optimum base was incorporated with model drug which was sildenafil citrate, sweetener and flavor. The final formulation is presented in Table 2. The preparation method was the same for heat-dried and freeze-dried methods as described above. Physical characterization and uniformity of drug content The final formulation was characterized physically using the characterization mentioned above and the drug content was determined using a HPLC-UV system. The HPLC system was comprised of a Shimadzu (VP series, Kyoto, Japan) pump (LC20AT vp) with solvent cabinet, a degasser (DGU-20A3), a column oven (CTO-10S VP), an auto-injector (SIL-20A HT vp), UV/VIS detector (SPD-20A vp) and a computer software (LC-Solution VP). The separation was carried out using a Synchronize C-18 column (150 4.6 mm ID, 5 mm) (Thermo Scientific, Waltham, MA). The flow rate was set at 1.5 mL/min, column temperature was set at 30 C and detection wavelength of 240 nm was used. Sample of 25 mL was injected onto the column. Ammonium acetate buffer solution (0.2 M) was mixed with acetonitrile at 1:1 ratio at pH 7.40. The mobile phase was stirred using a magnetic stirrer for 15 min. The pH of the mobile phase was checked using a pH meter. The mobile phase was then filtered through Whatman nylon membrane filters 0.45 mm using a filtration set. The filtered mixture was degassed using a sonicator for 15 min. A piece of ODF film (20 20 mm) was dissolved in mobile phase by sonication. After appropriate dilution, 25 mL of the sample was injected into the HPLC and the amount of drug was determined. Six ODF (20 20 mm) of each formulation were examined. Scanning electronic microscopy (SEM) SEM images were obtained using the scanning electron microscope (VE-7300, Keyence). The heat-dried and freeze-dried Sildenafil films were mounted on a metal stub with double-sided adhesive tapes. The sample was sputtered with a thin layer of gold to improve the electrical conductivity prior to imaging.
3
In vitro drug dissolution study The dissolution studies were carried out on the optimum heatdried and freeze-dried ODF formulation and the original product (ViagraÕ ). Drug dissolution study was carried out in 900 mL of phosphate buffer (pH 4.5 ± 0.1) at 37.0 ± 0.5 C, using USP basket method at a stirring speed of 100 rpm. At preset time intervals of 5, 10, 15, 20, 30, 45, 60, 90 and 120 min, 1 mL of samples were withdrawn and immediately replaced with an equal volume of fresh dissolution medium. The samples were filtered through 0.45 mm membrane filter and the amount of drug released was determined using a validated HPLC-UV method. Similarities between the dissolution profiles were assessed by a pair-wise model independent procedure, similarity factor (f2)18,19: 8" 9 #0:5 < = 1 f2 ¼ 50Log 1 þ Pn¼i 100 ð2Þ : ; n n¼1 ðRt Tt Þ2 where n is the number of pull points, wt is an optional weight factor, Rt is the reference profile at time point t and Tt is the test profile at the same time point; the value of f2 should be between 50 and 100. A f2 value of 100 suggests that the test and reference profiles are identical and dissimilarity between release profiles increases as the value becomes smaller. In situ disintegration time and palatability studies A total of 12 healthy adult volunteers with age between 22 and 55 years old participated in this study after providing written informed consent. Prior to the study, the volunteers were briefed on the nature, purpose, duration and risk of the study. The study protocol was approved by the University Human Research Ethics Committee (JePEM USM). Prior to the study, the volunteers were required to gargle their mouth with 200 mL of distilled water. One ODF was placed on the tongue of the volunteer. The volunteers were requested to give the score based on a five-points scale to evaluate three parameters namely taste, after taste and acceptance as stated in Table 3. The volunteers were told to spit out the test sample, followed by Table 3. Parameters and score in palatability study. Taste Very bitter Bitter Slightly bitter Slightly sweet Very sweet
Aftertaste
Acceptance
Score
Very bitter Bitter Slightly bitter Slightly sweet Very sweet
Very poor Poor Acceptable Good Very good
1 2 3 4 5
Table 2. Final formulation of ODF by heat-dried and freeze-dried methods.
Ingredient Sildenafil citrate Carbopol Wheat starch PEG 400 Sucralose Green apple flavor
Weight (g/50 mL of casting solution) 1.00 0.50 1.50 1.50 1.00 1.00
Figure 1. The photograph of sildenafil (A) heat-dried and (B) freeze-dried method.
ODF
prepared
using
Tensile strength (N/cm2) Folding endurance (times) Thickness (mm) Disintegration time (s)
Parameter
Tensile strength (N/cm2) Folding endurance (times) Thickness (mm) Disintegration time (s)
Parameter
Tensile strength (N/cm2) Folding endurance (times) Thickness (mm) Disintegration time (s)
Parameter
3.96 ± 1.22
799.83 ± 15.65
620.67 ± 1.75 143.50 ± 8.19
6.14 ± 1.03
780.17 ± 14.91
570.83 ± 2.14 161.67 ± 6.77
FD
610.17 ± 1.72 211.00 ± 7.92
561.00 ± 1.26 231.67 ± 8.45
F15
899.00 ± 15.62
877.83 ± 17.68
HD
6.88 ± 1.09
9.48 ± 1.19
FD
628.00 ± 2.45 271.17 ± 8.23
577.67 ± 1.37 290.33 ± 8.31
HD
861.83 ± 18.61
840.67 ± 19.20
F8
9.38 ± 1.71
FD
11.93 ± 1.86
HD
F1
F9
554.33 ± 1.75 174.50 ± 10.78
2.75 ± 1.28
FD
604.67 ± 1.51 148.00 ± 8.88
928.33 ± 15.65
4.74 ± 1.28
FD
604.33 ± 2.50 186.67 ± 7.42
752.67 ± 18.99
5.19 ± 0.48
FD
598.33 ± 3.44 124.67 ± 8.21
826.17 ± 11.89
F16
908.00 ± 16.66
7.10 ± 1.15
HD
555.67 ± 1.50 205.67 ± 7.00
732.67 ± 18.90
7.72 ± 0.71
HD
550.33 ± 1.86 143.50 ± 7.66
805.50 ± 11.29
4.98 ± 1.33
HD
F2
551.50 ± 2.17 221.33 ± 8.64
600.83 ± 1.94 201.50 ± 9.18
781.00 ± 11.63
6.34 ± 0.65
FD
625.83 ± 1.72 242.50 ± 9.35
977.17 ± 34.50
7.36 ± 1.06
FD
596.33 ± 2.16 138.67 ± 10.54
F17
759.00 ± 12.90
8.48 ± 0.93
HD
575.50 ± 1.52 262.50 ± 8.31
3.68 ± 0.53
FD
831.83 ± 7.52
F10
957.50 ± 35.46
10.27 ± 1.05
HD
547.33 ± 1.97 156.00 ± 7.82
811.00 ± 8.05
5.88 ± 0.68
HD
F3
561.50 ± 2.07 234.50 ± 9.14
612.33 ± 2.50 206.67 ± 12.96
896.50 ± 12.13
6.71 ± 1.22
FD
611.17 ± 1.83 212.17 ± 9.15
897.67 ± 10.17
6.67 ± 1.23
FD
621.33 ± 1.86 233.17 ± 9.83
F18
876.33 ± 10.97
9.11 ± 1.28
HD
562.00 ± 1.90 230.83 ± 9.75
7.48 ± 1.12
FD
951.00 ± 24.34
F11
878.33 ± 11.22
9.14 ± 1.20
HD
571.83 ± 2.14 252.50 ± 8.69
930.33 ± 24.78
9.91 ± 1.24
HD
F4
Formulation
3.37 ± 0.92
HD
561.17 ± 2.04 229.00 ± 9.12
875.50 ± 8.17
9.28 ± 0.91
HD
561.83 ± 1.47 232.17 ± 8.13
F5
1.62 ± 0.57
FD
6.88 ± 1.05
FD
610.17 ± 1.47 208.33 ± 9.54
894.83 ± 10.32
F19
610.50 ± 1.64 213.00 ± 8.67
898.17 ± 10.68
6.74 ± 1.21
FD
590.33 ± 2.42 109.33 ± 8.04
777.50 ± 18.73
F12
876.33 ± 13.81
9.12 ± 1.19
HD
539.17 ± 3.76 128.50 ± 9.69
757.00 ± 18.11
Table 4. The results of physical characterization of ODF prepared using heat-dried and freeze-dried methods. Mean ± SD, n ¼ 6.
590.50 ± 1.76 304.33 ± 7.06
9.52 ± 1.32
FD
639.33 ± 1.75 284.17 ± 7.17
813.17 ± 13.80
9.28 ± 0.89
FD
594.50 ± 2.43 112.67 ± 9.85
910.67 ± 23.00
2.49 ± 1.22
FD
535.83 ± 1.72 251.83 ± 7.88
842.67 ± 8.43
F20
793.83 ± 11.30
11.84 ± 0.89
HD
544.67 ± 1.63 136.17 ± 9.26
F6
F13
890.67 ± 22.72
4.44 ± 0.89
HD
586.67 ± 2.16 272.00 ± 7.72
822.17 ± 8.98
10.36 ± 1.22
HD
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560.67 ± 2.16 228.50 ± 8.17
10.00 ± 1.24
FD
610.17 ± 2.32 212.00 ± 9.21
896.33 ± 14.56
6.70 ± 1.23
FD
642.67 ± 2.16 295.00 ± 6.16
960.17 ± 24.59
F14
876.00 ± 12.70
9.18 ± 1.50
HD
593.83 ± 2.14 314.00 ± 6.23
940.50 ± 26.73
12.87 ± 1.28
HD
F7
4 K. B. Liew & M. A. Odeniyi Pharm Dev Technol, Early Online: 1–8
Freeze dried orally disintegrating films
DOI: 10.3109/10837450.2014.1003657
5
Table 5. Process variables used in Central Composite Design for oral dissolving films with the correspondent fit model and prediction equation for each parameter tested.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Fit model Predict equationa
Factor 1 A: Carbopol
Factor 2 B: Wheat starch
Factor 3 C: PEG 400
Response 1 Tensile strength (N/cm2)
Response 2 Disintegration time (s)
3.68 0.32 2.00 3.00 1.00 2.00 3.00 2.00 2.00 2.00 2.00 2.00 1.00 2.00 1.00 1.00 3.00 2.00 2.00 3.00
2.00 2.00 0.32 1.00 1.00 3.68 3.00 2.00 2.00 2.00 2.00 2.00 1.00 2.00 3.00 3.00 1.00 2.00 2.00 3.00
2.00 2.00 2.00 3.00 1.00 2.00 3.00 2.00 0.32 3.68 2.00 2.00 3.00 2.00 1.00 3.00 1.00 2.00 2.00 1.00
11.93 4.98 5.88 9.91 3.37 10.36 12.87 9.48 7.72 10.27 9.14 9.12 4.44 9.18 6.14 7.10 8.48 9.11 9.28 11.84 Linear ¼+220.48 + 54.06 A + 30.10 B + 11.49 C
290.33 143.5 156 252.5 128.5 272 314 231.67 205.67 262.5 230.83 232.17 136.17 228.5 161.67 174.5 221.33 234.5 229 304.33 Quadratic ¼+9.23 + 2.47A + 1.41 B + 0.64 C + 0.11 AB + 0.054 AC 0.064 BC 0.37 A2 0.49 B2 0.18 C2 0.9607 25.283
R2 Adeq. Precision
0.9151 26.519
a
A: Carbopol; B: Wheat starch; C: PEG 400.
Figure 2. Response surface plot for the effect of polymer concentration on the film tensile strength for oral disintegrating films.
14 12 10
hardness (kg)
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Formulations
8 6 4 2
3.00
3.00 2.50
2.50 2.00
2.00 1.50
B: Wheat starch
1.50 1.00
A: Carbopol
1.00
rinsing their mouths with 200 mL of distilled water. There was a wash out period for 2 h before the second formulation was administered on the same group of volunteers.
difference. For stability study, post hoc Dunnet’s test (two sided) was performed, comparing with zero month data. A statistically significant difference was considered at p50.05.
Statistical analysis
Results
The results were expressed as mean ± standard deviation (SD). Statistical Procedure for Social Science (SPSS), Ver 16.0 (SPSS Inc., Chicago, IL) was used for statistical analysis. The results obtained from physical evaluations were analyzed statistically using one-way analysis of variance (ANOVA). Post hoc TukeyHSD test was carried out when there was a statistically significant
The images of freeze-dried and heat-dried film are presented in Figure 1. Heat-dried film was transparent but freeze-dried film was white in color. The results of tensile strength, folding endurance, thickness and in vitro disintegration time are presented in Table 4. The experimental design employed in this study provided a predictable equation for each of the parameters
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K. B. Liew & M. A. Odeniyi
Pharm Dev Technol, Early Online: 1–8
Figure 3. Response surface plot for the effect of polymer concentration on the disintegration time for oral disintegration films.
350 300
dt (s)
250 200 150 100
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3.00 2.50 2.00 3.00
2.50
2.00
1.50 1.50
A: Carbopol
1.00 1.00
B: Wheat starch
examined, according to a refined model which can be found in Table 5. Generally, it was noted that film prepared using heatdried method has higher tensile strength than film prepared using freeze-dried method for the same formulation and the difference was statistically significant (p50.05). For folding endurance film prepared using freeze-dried method showed improved endurance than the same formulation prepared using heat-dried method and the difference was found statistically significant (p50.05). Moreover, film prepared using freeze-dried method was thicker and had faster disintegration time than the same formulation prepared using heat-dried method. Formulations with higher amount of carbopol and starch showed higher tensile strength and thickness whereas formulations with higher PEG 400 content showed better flexibility. The fitted model for the hardness of the ODT is linear and shows that the interaction terms are insignificant. However, a second order quadratic model best described the disintegration profile. The refined model was used for drawing contour plots, as shown in Figures 2 and 3, respectively. The results are very clear in distinguishing formulation f16 as the optimum in terms of ODT strength and disintegration time, and were used for the final formulation. Formulation f16 has the highest tensile strength among the formulations with in vitro disintegration time less than 180 s. The physical characterization and drug content of final formulation prepared using heat-dried and freeze-dried methods are presented in Table 6. The final formulation after incorporation of model drug, sweetener and flavor showed variation in physical characterization parameters. The tensile strength and folding endurance reduced while the disintegration time and thickness increased compared to the base. The drug content was within the close range of 98–102%. The SEM micrographs of the films are shown in Figure 4. The freeze-dried film showed more porous structure compared to the heat-dried film. The porosity formed as a result of the release of water molecule from the frozen structure when it was subjected to freeze drying process. As a result, the disintegration time of the freeze-dried film was shorter than the heat-dried film. It also explained the weaker tensile strength of the freeze-dried film. The drug dissolution profiles of heat-dried and freeze-dried ODF and ViagraÕ are presented in Figure 5. The three products released 80% of the drug content within 45 min.
Table 6. The results of physical characterization of final formulation of ODF prepared using heat-dried and freeze-dried methods. Mean ± SD, n ¼ 6. Formulation Parameter Tensile strength (N/cm2) Folding endurance (times) Thickness (mm) In vitro disintegration time (s) In situ disintegration time (s) Drug content (%) Palatability study (score) a. Taste b. Aftertaste c. Acceptance
HD
FD
6.67 ± 0.12 897.67 ± 5.92 585.67 ± 4.41 183.50 ± 4.04 176.50 ± 3.56 99.50 ± 0.72
4.41 ± 0.12 919.50 ± 3.94 634.83 ± 3.43 165.67 ± 4.03 156.00 ± 2.90 99.12 ± 0.75
4.38 ± 0.52 4.13 ± 0.64 4.75 ± 0.46
4.50 ± 0.53 4.25 ± 0.71 4.63 ± 0.52
Discussion The demand for orally disintegrating dosage forms has markedly increased because it provides a means of providing a patient friendly, economical and yet effective drug delivery system20. Oral disintegrating films are ultra-thin and flexible strips of postage stamp size films, with an active pharmaceutical ingredient or combination of active pharmaceutical ingredients, which disintegrate within a minute when in contact with water or saliva. They offer the advantages of large surface area, rapid onset of action, accuracy of dosage, taken without water and could be designed for specific groups of people to solve non-compliance issues5. Formulation 16 was chosen for the final formulation as it was the optimum base in terms of tensile strength and disintegration time. The preparation method was the same for heat-dried and freeze-dried methods with the sildenafil citrate, flavor and disintegrant incorporated. PEG 400 was incorporated as plasticizer to increase film flexibility as well as improve ease of film removal from the mould. There was no significant difference (p40.05) in the result of content uniformity (Table 5). The sildenafil citrate content in the formulations using the two different methods of formulation ranged from 99.12 ± 0.75% to 99.50 ± 0.72% of the theoretical
Freeze dried orally disintegrating films
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DOI: 10.3109/10837450.2014.1003657
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Figure 4. SEM micrograph of (A) heat-dried sildenafil film and (B) freeze-dried sildenafil film.
Figure 5. Dissolution profiles of heat-dried, freeze-dried sildenafil films and Viagra in 900 mL phosphate buffer (pH 4.5) using USP basket method with stirring speed at 100 rpm (mean ± sd, n ¼ 6).
concentration. This shows the suitability of both methods in producing formulations of uniform drug content. The ODF prepared using the heat drying method was significantly (p50.05) stronger than those prepared by freeze drying. Values of tensile strength were 6.67 ± 0.12 and 4.41 ± 0.12 N/cm2 for the heat-dried and freeze-dried formulations, respectively. Freeze-dried products have generally been found to be fluffy and weaker than comparable heat-dried products. These could be due to the freezing and drying technique employed. This prevents the formation of solid bridges characteristic of heat drying21. The tensile strength of the ODF was further assessed using film flexibility determination. The folding endurance results for the films from the two techniques employed showed the FD formulation to be more significantly flexible than the HD samples. However, ODF from both formulations did not show signs of crack after been folded 180 at the same place up to 800 times and the formulations could be defined as flexible and would be stable under pressure encountered during manufacture, transportation and handling22. The in vitro disintegration time was 183.50 ± 4.04 s for HD and 165.67 ± 4.03 s for the FD ODTs. The faster disintegration observed in the FD formulations could be attributed to greater water uptake due to the porous nature of the film structure. The in situ disintegration time for HD films was 176.50 ± 3.56 s
and 156.00 ± 2.90 s for FD ODFs. The results are similar to those obtained in vitro and suggest a correlation in in vitro/in situ disintegration properties of the films. The drug dissolution profiles of HD and FD ODF formulations and ViagraÕ are presented in Figure 3. The dissolution profiles for the three formulations were very similar with 80.0% of sildenafil citrate been released within 45 min in all the formulations. The similarity factor (f2) for HD and FD final formulations were 65.98 and 51.04, respectively. From the palatability evaluation, the final formulations of both HD and FD were found sweet in taste and after taste and acceptable. The freeze-dried formulations were very light and gave a highly porous structure which provided rapid disintegration. Also, the freeze drying process is accomplished at non-elevated temperatures and thus eliminating adverse thermal effects which may affect drug stability during processing in contrast to heat drying. Further, freeze drying may produce a glassy amorphous structure of excipients and the drug substance, hence improving the dissolution rate14.
Conclusion The results obtained from this work showed that: Oral disintegrating films of sildenafil citrate with good mechanical and release properties were prepared using freeze-drying and heat-dried technique. Freeze-dried films generally showed lower tensile strength, but better folding endurance and disintegration time compared to heat-dried film. Increase in carbopol and starch concentrations in the film formulations increased tensile strength and disintegration time. The films were found to have good palatability and masked the taste of the active ingredient in the formulation.
Declaration of interest The authors report no conflicts of interest The authors are grateful to TWAS, The World Academy of Sciences and Universiti Sains Malaysia for the TWAS-USM Postdoctoral Fellowship granted MAO.
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