http://informahealthcare.com/phd ISSN: 1083-7450 (print), 1097-9867 (electronic) Pharm Dev Technol, Early Online: 1–5 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10837450.2014.882936
RESEARCH ARTICLE
A new method for evaluating the dissolution of orodispersible films
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Yiran Xia, Fang Chen, Huiping Zhang, and Chunlin Luo National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, Zhangjiang Hi-Tech Park, Shanghai, People’s Republic of China Abstract
Keywords
The aim of this research was to develop and assess a new dissolution apparatus for orodispersible films (ODFs). The new apparatus was based on a flow-through cell design which requires only a limited amount of dissolution medium and can automatically collect samples in short-time intervals. Compared with the dissolution method in Chinese Pharmacopeia, our method simulated the flow condition of the oral cavity and resulted in reproducible dissolution data and remarkably discriminating capability. Therefore, we concluded that the proposed dissolution method was particularly suitable for evaluating the dissolution of ODFs and should also be applicable to other fast-dissolving solid dosage forms.
Dissolution method, drug release, orodispersible films, voglibose
Introduction Orodispersible film (ODF) is a new drug delivery system for orally disintegrating dosage forms. It generally has the appearance of an ultra-thin strip of a postage stamp size containing an active agent or active pharmaceutical ingredient and other excipients, including water-soluble polymers, which disintegrates or dissolves when placed onto the tongue1. Since Pfizer introduced Listerine PocketPaks thin strips in 2001 and InnoZen launched the first over-the-counter ODF Chloraseptic Relief Strips in 2003, there are more than 10 ODF products marketed in the past 10 years2. The ODF presents considerable advantages in improving compliance for those patients who have difficulties in swallowing because it can be rapidly wetted and adhered to the mucosa, and then completely dissolved in a short time. As ODFs are intended to dissolve rapidly in the mouth, the rate of dissolution in the oral cavity is certainly one of the most important performance characteristics. At present, the dissolution test for ODFs is routinely performed using the standard basket or paddle apparatus described in the pharmacopoeias3. There have also been several reports on the modified dissolution method of ODFs. Dinge et al.4 used 20 ml medium in a 50 ml glass beaker and utilized a shaft for agitation. Garsuch et al.5 introduced a fiber-optic sensor system to obtain more sampling readings in a shorter time, so that a method which closely followed the entire drug release duration may be achieved. However, these methods did not mimic the physiological conditions sufficiently. Disintegration tests were also employed to assess the performance of ODFs in medium, many of which were tailored to simulate the in vivo condition6–8. However, as the data obtained were based on subjective observations and
Address for correspondence: Yiran Xia, National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, 1111 Halei Road, Zhangjiang Hi-Tech Park, Shanghai 201203, People’s Republic of China. Tel: 86-21-51320211-8305. Fax: 86-2151320719. E-mail: [email protected]
History Received 7 August 2013 Revised 17 December 2013 Accepted 2 January 2014 Published online 31 January 2014
judgments, at best they might be used as a qualitative guideline at the dosage form development stage. It is, therefore, the objective of this study to establish a proper dissolution method for ODFs. A new dissolution device was designed by our group and ODF test samples were prepared based on voglibose (VB). VB is an alpha-glucosidase inhibitor for the lowering post-prandial blood glucose level in patients with diabetes mellitus. It is very soluble in water and has a low dose requirement of 0.2 and 0.3 mg. To demonstrate the utility of our approach, the ODF dissolution data from our method are compared with that obtained using the third dissolution method in Chinese Pharmacopeia (CP 2010, appendix XD).
Materials VB was obtained from Shanghai Techwell Biopharmaceutical Company (China). MethocelÔ E3, E5 and E15 (Dow Chemical, Midland, MI) and titanium dioxide powder (Shanghai Linsheng Refined Titanium Dioxide Company, China) were used as film formers. Acetonitrile (high-performance liquid chromatography (HPLC) grade), sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate dodecahydrate, taurine and sodium periodate were purchased from sinopharm chemical reagent (Shanghai, China).
Methods Preparation of oral films VB films were prepared by a solvent casting method. Briefly, an appropriate amount of the selected HPMC was dissolved in distilled water to a proper proportion, then VB and titanium dioxide were dissolved or dispensed into it under continuous stirring. The resulting film-forming solution was cast and dried on a pilot-scale machine constructed in our lab. For convenience, F1, F2 and F3 were designating films made of MethocelÔ E3, E5 and E15, respectively. The film composition is given in Table 1. The film thickness was controlled by adjusting the height of the blade
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in the casting machine, and was measured after drying using a micrometer caliper. In this study, films with thickness ranging from 35 to 65 mm were prepared and tested. Individual film samples were uniformly cut into 2.5 cm 1.5 cm pieces for further testing. Dissolution testing of VB films
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Dissolution method according to CP The third method, also called the small-cup method, was used to test the dissolution of VB films. It was like a miniature version of the paddle method with spherical support beaker of 250 mL. The dissolution medium was 100 ml distilled water, due to the sensitivity limit of the fluorescence response for such a low-dose film. The stirring rate was tested for 30, 50 and 100 rpm. Two pieces of sieve mesh with sieve opening of 0.2 cm were tied together to hold the film samples in place and to prevent it from floating to the top. The novel dissolution method Figure 1 is an illustration of the experimental setup of the new dissolution device constructed in our lab. Film samples were sandwiched between two pieces of sieve mesh with sieve opening of 0.1 cm and fixed in the right position of the sample cells.
Table 1. Composition of films. VB Film-polymers MethocelÔ E3 (F1) MethocelÔ E5 (F2) MethocelÔ E15 (F3) Titanium dioxide
1% 94% 5%
The cell size was 2.7 cm 1.5 cm 0.2 cm, which was especially designed for film to fit neatly into. Dissolution medium was loaded in syringe injectors and pre-heated to the desired temperature as the medium was pumped through a temperaturecontrolled heating plate before entering into the sample cells. The flow rate was controlled by the rotational speed of the servomotor and the diameter of the syringe. In this test, the dissolution medium flowed through a vertical sample cell from the bottom to the top to allow easy elimination of air bubbles. The timer began counting as the film was completely wetted. The sample collection tubes were fixed in the rack and moved automatically at predetermined time to collect the eluted dissolution medium. Six samples were collected simultaneously. Assessment of reproducibility of the proposed method To assess batch-to-batch variability, three pilot batches of F1 with 50 mm were prepared, and the drug release was assessed with our proposed dissolution method. The flow rate was set at 2.46 ml/min. VB assay VB analysis was carried out on a HPLC-fluorescence detection system (Shimadzu, Japan) with post-column derivatization as described in JP XVI. HPLC was performed on an NH2P-50 4 E column (250 4.6 mm, 5 mm, Shodex Asahipak). The mobile phase consisted of acetonitrile-20 mM sodium dihydrogen phosphate (adjusted to pH 6.8) at a ratio of 67:33 (v/v). The reaction reagent contained 6.25 mg/ml of taurine and 2.56 mg/ml of sodium periodate. The flow rate of mobile phase and reaction reagent was 1.0 ml/min. The column temperature was set at 40 C and the reaction temperature was 98 C. Detection was performed at an excitation wavelength of 350 nm and an emission wavelength of 430 nm.
Figure 1. Schematic drawing of the experimental setup of the new dissolution device.
A new method for evaluating the dissolution of orodispersible films
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Figure 4. Drug release profiles from films prepared with different HPMC grades using the small-cup method. Each point represents the mean ± SD of six experiments.
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Figure 3. Drug release profiles from F1 with different thickness using the small-cup method. Each point represents the mean ± SD of six experiments.
Evaluation of the dissolution of film-polymer in human volunteers F1 of 50-mm thickness was evaluated in healthy human volunteers with informed consent (n ¼ 10; 6 males and 4 females) for its in vivo behavior. The volunteers were asked to hold a piece of the test film sample on the tongue and move the tongue every 30 s to detect if any film fragment remained.
Results Drug release using the small-cup method When measured with the small-cup method, F1 of 50-mm thickness dissolved very fast (Figure 2). It completely dissolved in 1 min as the stirring rate was 100 rpm and in 1.5 min at the rate of 50 and 30 rpm. The rate of 30 rpm was chosen for further study in view of its slightly higher discriminatory power. Dissolution profiles of F1 with different thickness are shown in Figure 3, where it was clear that the dissolution rate of F1 samples decreased with increasing film thickness. F1 of 65-mm thickness took 3 min to complete release while the other two needed 1.5 min. This was most likely due to the longer time it took for the dissolution medium to penetrate and swell the thicker polymer film before it could be dissolved. On the other hand, as shown in Figure 4, films prepared with different grades of HPMC displayed different dissolution profiles for the same sample thickness of 50 mm. It can be seen from Figure 5 that F1 dissolved completely in 1.5 min while F2 and F3 dissolved in 2 and 3 min, respectively. This might be due to the higher polymer viscosity associated with HPMC of higher molecular weight which slowed the film swelling and dissolution.
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Figure 5. Drug release profiles from F1 with 50 mm using the proposed dissolution method at different flow rates. Each point represents the mean ± SD of six experiments.
Since MethocelÔ E is a group of water-soluble polymers, it is not surprising that VB films prepared from this HPMC grade could always dissolve within minutes. Drug release using our proposed new dissolution method The dissolution rate of the film was flow rate limited with the proposed method. For example, F1 of 50-mm thickness dissolved completely in about 10 min when the flow rate was 1.23 ml/min. As the flow rate doubled, time to reach complete dissolution decreased to one-third, requiring less than a total of 10 ml dissolution medium. As the flow rate quadrupled to 4.92 ml/min, the dissolution profile similar to that of the small-cup method at 30 rpm was observed (Figure 6), while consuming less than onesixth of the dissolution medium required for the small-cup method. It is clear that our proposed new dissolution method offers greater sensitivity and discriminating power through a small adjustment of the medium flow rate. Using the proposed new dissolution method, dissolution trends similar to that of Figure 3 were obtained between the thickness of ODFs and the dissolution rate. As shown in Figure 7, F1 of 35 and 50-mm thickness dissolved in about 2 min, whereas the thickest one of 65 mm took 5 min to dissolve. With the proposed new method, we also arrived at a conclusion that films made of HPMC with higher molecular weight exhibited slower dissolution rate (Figure 8). For example,
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Figure 9. Comparison of drug release profiles from F1 of three different batches. Each point represents the mean ± SD of six experiments.
produce consistent ODF dissolution results with minimum variability.
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Evaluation of the dissolution of film-polymer in human volunteers
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Figure 7. Drug release profiles from F1 with different thicknesses using the proposed new method. Each point represents the mean ± SD of six experiments.
The average time that F1 samples became non-detectable in the oral cavity was 2.3 min. The changes in integrity of F1 was also assessed visually when performing dissolution studies. It turned out that the time for complete polymer-dissolving and complete drug release was approximately identical which may due to the high solubility of VB. With the small-cup method, complete dissolution of filmpolymer was about 1.5 min even at a very low stirring speed (30 rpm), faster than the human results. In contrast, it dissolved in about 3 min at a flow rate of 2.46 ml/min with our proposed method, which was close to the in vivo results. One of the reasons may be that the small-cup method requires a much larger volume of dissolution medium with constant stirring which does not mimic the physiological conditions in humans.
Disscusion and conclusion
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Figure 8. Drug release profiles from films with different HPMC grades using the proposed new method. Each point represents the mean ± SD of six experiments.
F1 dissolved completely in about 2 min whereas F2 and F3 dissolved in 3 and 5 min, respectively. Assessment of reproducibility The proposed method resulted in reproducible dissolution data, with a coefficient of variation less than 5% at all-time points, and produced no significant difference among three batches of ODFs (Figure 9). This suggests that the proposed dissolution test should
The purpose of this study was to develop a simple and accurate dissolution method for in vitro evaluation of ODFs. VB films were prepared to assess our proposed dissolution method. There are some unique features of our proposed dissolution system. First, the device is efficiently designed and easy to assemble and disassemble, with a minimum built-in dead volume. Second, the introduction of a verticle sample cell design and the inclusion of suitable sieve mesh as film holder facilitate the more even flow of dissolution medium along the entire film surface and easier elimination of air bubbles from the cell. In our earlier attempts, horizontal cell design with larger dead volume and different sieve mesh sizes were tested. The data obtained were not optimal as the film dissolution tended to be slower or imcomplete because of insufficient rate of infiltration of the dissolution medium to rapidly conver the entire film sample surface. Third, the lack of convective agitation in this system resembles a relatively quiescent environment that a sublingual tablet or film may experience when it is held under the tongue and the flow rate can be easily adjusted to conform to the in vivo condition. Fourth, autosampling is implemented, which is critically important for the acquisition of dissolution data for fast-dissolving formulations. There was one proposed method characterizing the buccal dissolution of drugs which may appear to be closer to our idea9. It comprised a single, stirred, continuous flow-through filtration cell that included a dip tube to remove finely divided solid particles. However, the volume of liquid in the cell was
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DOI: 10.3109/10837450.2014.882936
A new method for evaluating the dissolution of orodispersible films
approximately 10 ml and the achievable flow rate was about 6 ml/ min. In our proposed method, the dead volume was decreased to a minimum of 0.8 ml and a flexible adjustment of the flow rate was achieved. In addition, our instrument design allowed for automatically sampling at small time intervals. Our study demonstrated that VB films dissolved too quickly using the small-cup method, thereby resulting in insufficient discriminating ability between samples. In addition, the small-cup method itself was not biorelevant. Our method, in contrast to the standard one, simulated the flow condition of the oral cavity10 and resulted in reproducible dissolution data and remarkably discriminating capability. Moreover, a reasonable correlation between in vitro drug release and in vivo film dissolution was observed. From this point of view, our proposed method presents a clear advantage, and should also be applicable to other dissolving-inthe-mouth type of solid dosage forms.
Acknowledgements The authors thank Professor Ping Lee of University of Toronto, Canada, for reading our manuscript and providing helpful suggestions.
Declareation of interest The research work was supported by the Fund of SINOPHARM (China National Medicines Corporation Ltd) (2011HY02) and Scientific and Technological Major Special Project ‘‘Significant Creation of New Drugs’’ – SINOPHARM Collaborative Technology Innovation Alliance Involving Production, Teaching and Research (2011ZX0940-403-3).
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References 1. Hariharan M, Bogue A. Orally dissolving film strips (ODFS): the final evolution of orally dissolving dosage forms. Drug Deliv Technol 2009;139:24–29. 2. Hoffmann EM, Breitenbach A, Breitkreutz J. Advances in orodispersible films for drug delivery. Expert Opin Drug Deliv 2011;8:299–316. 3. Dixit RP, Puthli SP. Oral strip technology: overview and future potential. J Controlled Release 2009;139:94–107. 4. Dinge A, Nagarsenker M. Formulation and evaluation of fast dissolving films for delivery of triclosan to the oral cavity. AAPS PharmSciTech 2008;9:349–356. 5. Garsuch V, Breitkreutz J. Novel analytical of oral wafers. Eur J Pharm Biopharm 2009;73:195–201. 6. Arya A, Chandra A, Sharma V, Pathak K. Fast dissolving oral films: an innovative drug delivery system and dosage form. Int J ChemTech Res 2010;2:576–583. 7. Garsuch V, Breitkreutz J. Comparative investigations on different polymers for the preparation of fast-dissolving oral films. J Pharm Pharmacol 2010;62:539–545. 8. Mishra R, Amin A. Formulation development of taste-masked rapidly dissolving films of cetirizine hydrochloride. Pharm Technol 2009;33:48–56. 9. Hughes L, Gehris A. A new method of characterizing the buccal dissolution of drugs, Rohm and Haas Research Laboratories-Spring House. Available from: https://www. rohmhaas.com/ionexchange/ Pharmaceuticals/Formulations_doc/buccal_dissolution.pdf [last accessed 12 Apr 2009]. 10. Humphrey SP, Williamson RT. A review of saliva: normal composition, flow, and function. J Prosthet Dent 2001;85: 162–169.
RESEARCH ARTICLE
A new method for evaluating the dissolution of orodispersible films
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Yiran Xia, Fang Chen, Huiping Zhang, and Chunlin Luo National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, Zhangjiang Hi-Tech Park, Shanghai, People’s Republic of China Abstract
Keywords
The aim of this research was to develop and assess a new dissolution apparatus for orodispersible films (ODFs). The new apparatus was based on a flow-through cell design which requires only a limited amount of dissolution medium and can automatically collect samples in short-time intervals. Compared with the dissolution method in Chinese Pharmacopeia, our method simulated the flow condition of the oral cavity and resulted in reproducible dissolution data and remarkably discriminating capability. Therefore, we concluded that the proposed dissolution method was particularly suitable for evaluating the dissolution of ODFs and should also be applicable to other fast-dissolving solid dosage forms.
Dissolution method, drug release, orodispersible films, voglibose
Introduction Orodispersible film (ODF) is a new drug delivery system for orally disintegrating dosage forms. It generally has the appearance of an ultra-thin strip of a postage stamp size containing an active agent or active pharmaceutical ingredient and other excipients, including water-soluble polymers, which disintegrates or dissolves when placed onto the tongue1. Since Pfizer introduced Listerine PocketPaks thin strips in 2001 and InnoZen launched the first over-the-counter ODF Chloraseptic Relief Strips in 2003, there are more than 10 ODF products marketed in the past 10 years2. The ODF presents considerable advantages in improving compliance for those patients who have difficulties in swallowing because it can be rapidly wetted and adhered to the mucosa, and then completely dissolved in a short time. As ODFs are intended to dissolve rapidly in the mouth, the rate of dissolution in the oral cavity is certainly one of the most important performance characteristics. At present, the dissolution test for ODFs is routinely performed using the standard basket or paddle apparatus described in the pharmacopoeias3. There have also been several reports on the modified dissolution method of ODFs. Dinge et al.4 used 20 ml medium in a 50 ml glass beaker and utilized a shaft for agitation. Garsuch et al.5 introduced a fiber-optic sensor system to obtain more sampling readings in a shorter time, so that a method which closely followed the entire drug release duration may be achieved. However, these methods did not mimic the physiological conditions sufficiently. Disintegration tests were also employed to assess the performance of ODFs in medium, many of which were tailored to simulate the in vivo condition6–8. However, as the data obtained were based on subjective observations and
Address for correspondence: Yiran Xia, National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, 1111 Halei Road, Zhangjiang Hi-Tech Park, Shanghai 201203, People’s Republic of China. Tel: 86-21-51320211-8305. Fax: 86-2151320719. E-mail: [email protected]
History Received 7 August 2013 Revised 17 December 2013 Accepted 2 January 2014 Published online 31 January 2014
judgments, at best they might be used as a qualitative guideline at the dosage form development stage. It is, therefore, the objective of this study to establish a proper dissolution method for ODFs. A new dissolution device was designed by our group and ODF test samples were prepared based on voglibose (VB). VB is an alpha-glucosidase inhibitor for the lowering post-prandial blood glucose level in patients with diabetes mellitus. It is very soluble in water and has a low dose requirement of 0.2 and 0.3 mg. To demonstrate the utility of our approach, the ODF dissolution data from our method are compared with that obtained using the third dissolution method in Chinese Pharmacopeia (CP 2010, appendix XD).
Materials VB was obtained from Shanghai Techwell Biopharmaceutical Company (China). MethocelÔ E3, E5 and E15 (Dow Chemical, Midland, MI) and titanium dioxide powder (Shanghai Linsheng Refined Titanium Dioxide Company, China) were used as film formers. Acetonitrile (high-performance liquid chromatography (HPLC) grade), sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate dodecahydrate, taurine and sodium periodate were purchased from sinopharm chemical reagent (Shanghai, China).
Methods Preparation of oral films VB films were prepared by a solvent casting method. Briefly, an appropriate amount of the selected HPMC was dissolved in distilled water to a proper proportion, then VB and titanium dioxide were dissolved or dispensed into it under continuous stirring. The resulting film-forming solution was cast and dried on a pilot-scale machine constructed in our lab. For convenience, F1, F2 and F3 were designating films made of MethocelÔ E3, E5 and E15, respectively. The film composition is given in Table 1. The film thickness was controlled by adjusting the height of the blade
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in the casting machine, and was measured after drying using a micrometer caliper. In this study, films with thickness ranging from 35 to 65 mm were prepared and tested. Individual film samples were uniformly cut into 2.5 cm 1.5 cm pieces for further testing. Dissolution testing of VB films
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Dissolution method according to CP The third method, also called the small-cup method, was used to test the dissolution of VB films. It was like a miniature version of the paddle method with spherical support beaker of 250 mL. The dissolution medium was 100 ml distilled water, due to the sensitivity limit of the fluorescence response for such a low-dose film. The stirring rate was tested for 30, 50 and 100 rpm. Two pieces of sieve mesh with sieve opening of 0.2 cm were tied together to hold the film samples in place and to prevent it from floating to the top. The novel dissolution method Figure 1 is an illustration of the experimental setup of the new dissolution device constructed in our lab. Film samples were sandwiched between two pieces of sieve mesh with sieve opening of 0.1 cm and fixed in the right position of the sample cells.
Table 1. Composition of films. VB Film-polymers MethocelÔ E3 (F1) MethocelÔ E5 (F2) MethocelÔ E15 (F3) Titanium dioxide
1% 94% 5%
The cell size was 2.7 cm 1.5 cm 0.2 cm, which was especially designed for film to fit neatly into. Dissolution medium was loaded in syringe injectors and pre-heated to the desired temperature as the medium was pumped through a temperaturecontrolled heating plate before entering into the sample cells. The flow rate was controlled by the rotational speed of the servomotor and the diameter of the syringe. In this test, the dissolution medium flowed through a vertical sample cell from the bottom to the top to allow easy elimination of air bubbles. The timer began counting as the film was completely wetted. The sample collection tubes were fixed in the rack and moved automatically at predetermined time to collect the eluted dissolution medium. Six samples were collected simultaneously. Assessment of reproducibility of the proposed method To assess batch-to-batch variability, three pilot batches of F1 with 50 mm were prepared, and the drug release was assessed with our proposed dissolution method. The flow rate was set at 2.46 ml/min. VB assay VB analysis was carried out on a HPLC-fluorescence detection system (Shimadzu, Japan) with post-column derivatization as described in JP XVI. HPLC was performed on an NH2P-50 4 E column (250 4.6 mm, 5 mm, Shodex Asahipak). The mobile phase consisted of acetonitrile-20 mM sodium dihydrogen phosphate (adjusted to pH 6.8) at a ratio of 67:33 (v/v). The reaction reagent contained 6.25 mg/ml of taurine and 2.56 mg/ml of sodium periodate. The flow rate of mobile phase and reaction reagent was 1.0 ml/min. The column temperature was set at 40 C and the reaction temperature was 98 C. Detection was performed at an excitation wavelength of 350 nm and an emission wavelength of 430 nm.
Figure 1. Schematic drawing of the experimental setup of the new dissolution device.
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Figure 4. Drug release profiles from films prepared with different HPMC grades using the small-cup method. Each point represents the mean ± SD of six experiments.
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Evaluation of the dissolution of film-polymer in human volunteers F1 of 50-mm thickness was evaluated in healthy human volunteers with informed consent (n ¼ 10; 6 males and 4 females) for its in vivo behavior. The volunteers were asked to hold a piece of the test film sample on the tongue and move the tongue every 30 s to detect if any film fragment remained.
Results Drug release using the small-cup method When measured with the small-cup method, F1 of 50-mm thickness dissolved very fast (Figure 2). It completely dissolved in 1 min as the stirring rate was 100 rpm and in 1.5 min at the rate of 50 and 30 rpm. The rate of 30 rpm was chosen for further study in view of its slightly higher discriminatory power. Dissolution profiles of F1 with different thickness are shown in Figure 3, where it was clear that the dissolution rate of F1 samples decreased with increasing film thickness. F1 of 65-mm thickness took 3 min to complete release while the other two needed 1.5 min. This was most likely due to the longer time it took for the dissolution medium to penetrate and swell the thicker polymer film before it could be dissolved. On the other hand, as shown in Figure 4, films prepared with different grades of HPMC displayed different dissolution profiles for the same sample thickness of 50 mm. It can be seen from Figure 5 that F1 dissolved completely in 1.5 min while F2 and F3 dissolved in 2 and 3 min, respectively. This might be due to the higher polymer viscosity associated with HPMC of higher molecular weight which slowed the film swelling and dissolution.
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Figure 5. Drug release profiles from F1 with 50 mm using the proposed dissolution method at different flow rates. Each point represents the mean ± SD of six experiments.
Since MethocelÔ E is a group of water-soluble polymers, it is not surprising that VB films prepared from this HPMC grade could always dissolve within minutes. Drug release using our proposed new dissolution method The dissolution rate of the film was flow rate limited with the proposed method. For example, F1 of 50-mm thickness dissolved completely in about 10 min when the flow rate was 1.23 ml/min. As the flow rate doubled, time to reach complete dissolution decreased to one-third, requiring less than a total of 10 ml dissolution medium. As the flow rate quadrupled to 4.92 ml/min, the dissolution profile similar to that of the small-cup method at 30 rpm was observed (Figure 6), while consuming less than onesixth of the dissolution medium required for the small-cup method. It is clear that our proposed new dissolution method offers greater sensitivity and discriminating power through a small adjustment of the medium flow rate. Using the proposed new dissolution method, dissolution trends similar to that of Figure 3 were obtained between the thickness of ODFs and the dissolution rate. As shown in Figure 7, F1 of 35 and 50-mm thickness dissolved in about 2 min, whereas the thickest one of 65 mm took 5 min to dissolve. With the proposed new method, we also arrived at a conclusion that films made of HPMC with higher molecular weight exhibited slower dissolution rate (Figure 8). For example,
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Figure 9. Comparison of drug release profiles from F1 of three different batches. Each point represents the mean ± SD of six experiments.
produce consistent ODF dissolution results with minimum variability.
120% 100% drug release (%)
0% 0
Figure 6. Comparation of the dissolution of F1 with the small-cup method and the proposed new method. Each point represents the mean ± SD of six experiments.
Evaluation of the dissolution of film-polymer in human volunteers
80% 60% 35µm,2.46ml/min 40% 50µm,2.46ml/min 20%
65µm,2.46ml/min
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Figure 7. Drug release profiles from F1 with different thicknesses using the proposed new method. Each point represents the mean ± SD of six experiments.
The average time that F1 samples became non-detectable in the oral cavity was 2.3 min. The changes in integrity of F1 was also assessed visually when performing dissolution studies. It turned out that the time for complete polymer-dissolving and complete drug release was approximately identical which may due to the high solubility of VB. With the small-cup method, complete dissolution of filmpolymer was about 1.5 min even at a very low stirring speed (30 rpm), faster than the human results. In contrast, it dissolved in about 3 min at a flow rate of 2.46 ml/min with our proposed method, which was close to the in vivo results. One of the reasons may be that the small-cup method requires a much larger volume of dissolution medium with constant stirring which does not mimic the physiological conditions in humans.
Disscusion and conclusion
120.0% 100.0% drug release (%)
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me (min)
80.0% 60.0% F1,2.46ml/min
40.0%
F2,2.46ml/min 20.0%
F3,2.46ml/min
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Figure 8. Drug release profiles from films with different HPMC grades using the proposed new method. Each point represents the mean ± SD of six experiments.
F1 dissolved completely in about 2 min whereas F2 and F3 dissolved in 3 and 5 min, respectively. Assessment of reproducibility The proposed method resulted in reproducible dissolution data, with a coefficient of variation less than 5% at all-time points, and produced no significant difference among three batches of ODFs (Figure 9). This suggests that the proposed dissolution test should
The purpose of this study was to develop a simple and accurate dissolution method for in vitro evaluation of ODFs. VB films were prepared to assess our proposed dissolution method. There are some unique features of our proposed dissolution system. First, the device is efficiently designed and easy to assemble and disassemble, with a minimum built-in dead volume. Second, the introduction of a verticle sample cell design and the inclusion of suitable sieve mesh as film holder facilitate the more even flow of dissolution medium along the entire film surface and easier elimination of air bubbles from the cell. In our earlier attempts, horizontal cell design with larger dead volume and different sieve mesh sizes were tested. The data obtained were not optimal as the film dissolution tended to be slower or imcomplete because of insufficient rate of infiltration of the dissolution medium to rapidly conver the entire film sample surface. Third, the lack of convective agitation in this system resembles a relatively quiescent environment that a sublingual tablet or film may experience when it is held under the tongue and the flow rate can be easily adjusted to conform to the in vivo condition. Fourth, autosampling is implemented, which is critically important for the acquisition of dissolution data for fast-dissolving formulations. There was one proposed method characterizing the buccal dissolution of drugs which may appear to be closer to our idea9. It comprised a single, stirred, continuous flow-through filtration cell that included a dip tube to remove finely divided solid particles. However, the volume of liquid in the cell was
Pharmaceutical Development and Technology Downloaded from informahealthcare.com by Purdue University on 08/28/14 For personal use only.
DOI: 10.3109/10837450.2014.882936
A new method for evaluating the dissolution of orodispersible films
approximately 10 ml and the achievable flow rate was about 6 ml/ min. In our proposed method, the dead volume was decreased to a minimum of 0.8 ml and a flexible adjustment of the flow rate was achieved. In addition, our instrument design allowed for automatically sampling at small time intervals. Our study demonstrated that VB films dissolved too quickly using the small-cup method, thereby resulting in insufficient discriminating ability between samples. In addition, the small-cup method itself was not biorelevant. Our method, in contrast to the standard one, simulated the flow condition of the oral cavity10 and resulted in reproducible dissolution data and remarkably discriminating capability. Moreover, a reasonable correlation between in vitro drug release and in vivo film dissolution was observed. From this point of view, our proposed method presents a clear advantage, and should also be applicable to other dissolving-inthe-mouth type of solid dosage forms.
Acknowledgements The authors thank Professor Ping Lee of University of Toronto, Canada, for reading our manuscript and providing helpful suggestions.
Declareation of interest The research work was supported by the Fund of SINOPHARM (China National Medicines Corporation Ltd) (2011HY02) and Scientific and Technological Major Special Project ‘‘Significant Creation of New Drugs’’ – SINOPHARM Collaborative Technology Innovation Alliance Involving Production, Teaching and Research (2011ZX0940-403-3).
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