Objective: The present study was done to understand the effect of formulation variables on the quality of orodispersible films using quality by design (QbD) approach as mentioned in ICH Q8 (R2) guideline.Methods: A definitive screening design of experiments (DoE) was used to identify and classify the critical formulation variables affecting critical quality attributes (CQA) using 2Ã—2 factorial design. Based on prescreening study, the critical formulation variables, i.e. concentration of film-forming polymer and plasticizers (propylene glycol and polyethylene glycol 400 [PEG 400]) were kept in the range of 1.5â€“2.5% w/w and 0.5â€“1% v/v, respectively. A total of eight laboratory-scale formulations were prepared which were provided by DoE using solvent casting method. These batches were evaluated for CQA's, i.e. mechanical properties such as folding endurance (FD) and disintegration time (DT). Data were analyzed for elucidating interactions between two variables and for providing a predictive model for the process. Finally, the drug was incorporated into optimized batches, and these were evaluated for in vitro dissolution study in simulated saliva (pH 6.8) as well as their mechanical properties.Results: The results suggested that the concentration of film-forming polymer and plasticizer was critical to manufacture orodispersible film with desired CQA, i.e. mechanical property (FD [&gt;150 folds]) and DT (&lt;60 s). The percent drug release, FD, and DT of optimized Formulation I (hydroxypropyl methylcellulose [HPMC] E5 (2%) and propylene glycol [0.15 mL]) were found to be 82.13%Â±0.260 (in 15 min), 164Â±2, and 49Â±1.5 s, respectively, and for optimized Formulation II (HPMC E5 [2%] and PEG 400 [0.15 mL]) was found to be 64.26%Â±2.026 (in 15 min) and 218Â±6 and 55Â±4 s, respectively.Conclusion: From the results, it has been found that the percentage drug release of naratriptan hydrochloride containing propylene glycol as a plasticizer was greater than the formulation containing PEG 400 as plasticizer. From this, we concluded that QbD is very much useful approach to get an optimized formulation in an economic and faster way in comparison to traditional method (hit and trail methods). The futuristic application of the film will involve the management of an acute migraine

Gupta, Ashutosh

Kumar, Jatin

Singh, Harmanpreet

Verma, Surajpal

English

Innovare Academic Sciences: E-Journals

Vol 11, Special issue 2, 2018Online - 2455-3891 Print - 0974-2441APPLICATION OF QUALITY BY DESIGN APPROACH FOR THE OPTIMIZATION OF ORODISPERSIBLE FILM FORMULATIONASHUTOSH GUPTA, JATIN KUMAR, SURAJPAL VERMA*, HARMANPREET SINGH*Department of Pharmaceutics, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India. Email: surajpal.15834@lpu.co.inReceived: 10 February 2018, Revised and Accepted: 20 February 2018ABSTRACTObjective: The present study was done to understand the effect of formulation variables on the quality of orodispersible films using quality by design (QbD) approach as mentioned in ICH Q8 (R2) guideline.Methods: A definitive screening design of experiments (DoE) was used to identify and classify the critical formulation variables affecting critical quality attributes (CQA) using 2×2 factorial design. Based on prescreening study, the critical formulation variables, i.e. concentration of film-forming polymer and plasticizers (propylene glycol and polyethylene glycol 400 [PEG 400]) were kept in the range of 1.5–2.5% w/w and 0.5–1% v/v, respectively. A total of eight laboratory-scale formulations were prepared which were provided by DoE using solvent casting method. These batches were evaluated for CQA’s, i.e. mechanical properties such as folding endurance (FD) and disintegration time (DT). Data were analyzed for elucidating interactions between two variables and for providing a predictive model for the process. Finally, the drug was incorporated into optimized batches, and these were evaluated for in vitro dissolution study in simulated saliva (pH 6.8) as well as their mechanical properties.Results: The results suggested that the concentration of film-forming polymer and plasticizer was critical to manufacture orodispersible film with desired CQA, i.e. mechanical property (FD [>150 folds]) and DT (<60 s). The percent drug release, FD, and DT of optimized Formulation I (hydroxypropyl methylcellulose [HPMC] E5 (2%) and propylene glycol [0.15 mL]) were found to be 82.13%±0.260 (in 15 min), 164±2, and 49±1.5 s, respectively, and for optimized Formulation II (HPMC E5 [2%] and PEG 400 [0.15 mL]) was found to be 64.26%±2.026 (in 15 min) and 218±6 and 55±4 s, respectively.Conclusion: From the results, it has been found that the percentage drug release of naratriptan hydrochloride containing propylene glycol as a plasticizer was greater than the formulation containing PEG 400 as plasticizer. From this, we concluded that QbD is very much useful approach to get an optimized formulation in an economic and faster way in comparison to traditional method (hit and trail methods). The futuristic application of the film will involve the management of an acute migraine.Keywords: Quality by design, Design of experiments, Critical quality attributes, Folding endurance, Naratriptan hydrochloride, Migraine.INTRODUCTIONIn the past few years, the pharmaceutical company or researchers mainly focus on those drug delivery systems, which provide faster onset of action of drug, enhanced bioavailability, and high patient compliance [1]. Nowadays, the best route for the administration of drug is oral as compared to other drug delivery route [2]. From all the dosage forms available in the market, there is a one solid dosage form, which has a high potential, and it also, fulfills these requirements are orodispersible films [3]. According to the Borges et al., the patients who are suffering from dysphagia, orodispersible film approach is very beneficial and useful for the delivery of the drug. Orodispersible film offers some features such as portability, stability, and flexibility, which confer superiority over the orodispersible capsules, and tablets [4]. An orodispersible films are very thin with the shape of postage stamp containing active pharmaceutical ingredient, polymers, and with or without plasticizers. An orodispersible film when placed onto the mucosal surface instantly gets wetted with saliva. After wetting it rapidly disintegrate and release its medicament [5]. The drawbacks of orodispersible films include moisture sensitivity, extreme temperature, high loading dose problem, and requirement of costly packaging [6].Advantages of orodispersible film•	 Quick	onset	of	action•	 Enhance	bioavailability•	 Avoid	first	pass	metabolism•	 Ease	of	transportation	and	handling•	 Taste	masking•	 No	such	apparatus	is	required	for	the	preparation•	 Site-specific	and	local	action	[7].The pharmaceutical quality by design (QbD) is a systemic approach to development that begins with the predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management [8].Critical process parameter (CPP) whose variability has an impact on a critical quality attributes (CQA) and therefore should be monitored or controlled to ensure the process produces the desired quality.CQA are chemical, physical, biological, and microbiological attributes that can be defined, measured, and continually monitored to ensure final product outputs remain within acceptable quality limits.Acute migraine is a disabling disorder characterized by moderate to severe throbbing, pulsating pain often associated with photophobia, phonophobia, nausea, and vomiting. It worsens with day to day activity of patient [9,10]. An untreated migraine attack can past for	 4–72	 h	 [11,12].	 Sexual	 dimorphism	 is	 reported	 in	 migraine,	i.e.	prevalence	ratio	among	men	and	women	is	3:7	[13,14].There are two approaches through which we can manage migraine, i.e. symptomatic therapy which further divided into two, i.e. use of non-specific drugs and specific drugs (ergot alkaloids and triptans), depends ©	2018	The	Authors.	Published	by	Innovare	Academic	Sciences	Pvt	Ltd.	This	is	an	open	access	article	under	the	CC	BY	license	(http://creativecommons.	org/licenses/by/4. 0/) DOI: http://dx.doi.org/10.22159/ajpcr.2018.v11s2.28508Research ArticleRecent	Trends	in	Biomedical	Sciences-2018		(RTBS-2018)9 Gupta et al.Asian J Pharm Clin Res, Vol 11, Special issue 2, 2018, 8-11on the efficacy of migraine attack. The second approach is preventative therapy, in which doctor gives the suggestion about daily life routine to the patients [15]. There are majorly conventional tablets available in the market, which is used for management of an acute migraine. Our film has more advantage over that as discussed above.Naratriptan is a serotonin 5-HT1B/1D receptor agonist and is used for the treatment of acute migraine. Activation of 5-HT1B receptor, which is present on the vascular smooth muscles, causes vasoconstriction of smooth muscles [16]. Activation of 5-HT1D which is located on the sensory trigeminal terminals inhibits the release of sensory and vasoactive	neuropeptides	and	vasodilator	transmitters	[17,18].MATERIALS AND METHODSNaratriptan hydrochloride was obtained as gift samples from Apotex Pharmachem Pvt., Ltd., India. Hydroxypropyl methylcellulose (HPMC) E5, propylene glycol, and polyethylene glycol 400 (PEG 400) were purchased from Loba Chemie. All other chemicals and reagents used were of analytical grade.Preparation of orodispersible placebo filmSolvent	 casting	 method	 was	 used	 for	 the	 preparation	 of	 film.	 In	 this	method initially, all the polymers are dissolved in the suitable solvent, and the drug and other additives are mixed in the other beaker containing suitable solvent. After that mix both the solution and stir it for some time. Then, the solution is subjected to the sonicator to eradicate the air bubble. Finally, that solution is transferred into Teflon or glass Petri plate and then placed in an oven for overnight at 50–60°C for drying. Peel out the film and kept in the desiccator till further use (Fig. 1) [19]. The film was cut in a piece of 3×1 cm2 for further evaluation with the help of surgical blade.QbD approach to develop orodispersible placebo filmA definitive screening design of experiments (DoE) was used to identify and classify the CPP affecting CQA using 2×2 factorial design. In this research study, we have considered CPP is concentration of HPMC E5, propylene glycol, and PEG 400. From the literature, we get to know about the concentration of above through which, good film was obtained with desired outcomes. If we increase the concentration of polymer, then there would be problem takes place during pouring, and resulting film is too thick. If we decrease the concentration, film becomes too thin, and it does not give desired outcomes. The main purpose of focusing disintegration time (DT) and folding endurance (FD) as CQA because if the DT is more than 60 s, then there may be chances that patient may split it. This is reason we get eight batches after applying DoE (Figs. 2 and 3).Evaluation of orodispersible placebo filmFDIt is the number of times a film could be folded manually at the same place without getting crack on it. It was checked by folding each film repeatedly at the same place until it breaks or folding it for 150 times whichever is less [20].In vitro DTIt tells about the disintegration and dissolution features of the film. Films from each batch of dimensions 3 cm × 1 cm2 was put in a Petri dish (6.5 cm diameter) having 25 ml of simulated saliva, maintained at 37°C,	with	agitation	at	every	10	s.	The	DT	was	recorded	when	the	film	starts to break or disintegrate [21].Preparation of optimized orodispersible film containing naratriptan hydrochlorideAfter analyzing the observations of 8 batches in DoE (Table 1); finally, we got the optimized concentration of polymer and plasticizer for the final formulation in which we had incorporated naratriptan hydrochloride. Accurately weigh 10 mg of drug and placed into the beaker containing 10 mL of water. Then, the solution was subjected to magnetic stirrer for dissolving the drug completely followed by addition of remaining additives. Further, the procedure was same as discussed above for the preparation of orodispersible placebo film.Fig. 1: Solvent casting methodFig. 2: Contour plot (optimization concentrations of hydroxypropyl methylcellulose E5 [2% w/v] and propylene glycol (0.15 mL)]Fig. 3: Contour plot (optimization concentrations of hydroxypropyl methylcellulose E5 [2%w/v] and polyethylene glycol 400 [0.15 mL])10 Gupta et al.Asian J Pharm Clin Res, Vol 11, Special issue 2, 2018, 8-11Evaluation of optimized formulation (Table 2)FD and in vitro DTThe folding endurance (FD) and in vitro disintegration time (DT) studies were performed as per the procedures mentioned under the title - Evaluation of orodispersible placebo film.In vitro drug releaseThe in vitro drug release was carried out in 250 ml of simulated saliva	 as	 dissolution	 medium	 using	 USP	 dissolution	 apparatus	 I,	maintained	 at	 37±0.5°C	with	 100	 rpm.	 10	ml	 samples	were	 taken	at different predetermined time intervals, and the same amount of fresh dissolution medium maintained at same temperature was added to maintain the sink condition in the dissolution vessel. Samples	were	passed	through	0.45	µm	membrane	filter	after	suitable dilutions, if required and then analyzed spectrophotometrically. It was conducted 3 times for each film formulation, and the average value was taken [22].RESULTSThe resultant formulation was transparent with a smooth texture. The outcomes of the resultant formulation are being tabulated below:Optimized Formulation I contains the drug, hydroxypropyl methylcellulose (HPMC) E5 and propylene glycol, optimized Formulation II contains the drug, HPMC E5, and polyethylene glycol 400CONCLUSION AND DISCUSSIONFrom the literature review, we came to know that using the concentration of polymer between 1.5% w/v and 2.5%w/v and plasticizer 0.1–0.2 mL, we will get the required FD, i.e. >150 folds and DT <1 min. We used same concentration of polymer and plasticizer, after that applied QbD. After applying QbD, we got an optimized formulations which show the required outcomes, i.e. FD >150 folds and DT <1 min (Table 3 and 4). We had done the in vitro dissolution study of both optimized batches, and from the results (Table 5 and 6), it had been concluded the percentage drug release of naratriptan hydrochloride in the optimized Formulation I after 15 min was >80% (Fig. 4). Hence, from this, we selected Formulation I for further study. From this, we concluded that QbD is very much useful approach to get an optimized formulation.Fig. 4: In vitro drug release comparison between optimized Formulation I and optimized Formulation II. Table 2: Results of prepared placebo films (n=3)Formulation DT (s) (mean±SD) FD (No.) (mean±SD)F1 40±2 135±5F2 42±1 164±4F3 50±3 223±1F4 55±1 112±3F5 50±2 192±4F6 70±1 191±5F7 57±1 350±2F8	formulation	was	too	sticky	that	is	why	not	being	peeled	out.	SD:	Standard	deviation, FD: Folding enduranceTable 3: Comparison between predicted and observed value of optimized formulation of HPMC E5 and Propylene glycol (n=3)Responses Predicted value Observed value (mean±SD)DT (s) 46.75 49±1.5FD (no.) 158.5 164±2HPMC:	Hydroxypropyl	methylcellulose,	SD:	Standard	deviation,	FD:	Folding	enduranceTable 4: Comparison between predicted and observed value of optimized formulation of HPMC E5 and PEG 400 (n=3)Responses Predicted value Observed value (mean±SD)DT (s) 58 55±4FD (no.) 222 218±6PEG 400: Polyethylene glycol 400, HPMC: Hydroxypropyl methylcellulose, SD:	Standard	deviation,	FD:	Folding	enduranceTable 5: In vitro drug release of the film of HPMC E5 and propylene glycol (n=3)Time (min) Absorbance  (mean±SD)Conc. (μg/mL)  (mean±SD)Corrected conc  (μg/mL) (mean±SD)Amount of drug (mg)  (mean±SD)% drug release  (mean±SD)0 0 0 0 0 02 0.101±0.002 0.4803±0.020 0.4803±0.020 0.1200±0.005 41.29±1.7305 0.119±0.003 0.6619±0.030 0.6715±0.030 0.1676±0.007 57.75±2.65010 0.131±0.001 0.7830±0.010 0.8024±0.004 0.200±0.001 69.01±0.34015 0.145±0.001 0.9243±0.010 0.9549±0.006 0.238v0.002 82.13±0.26020 0.149±0.002 0.9646±0.020 1.021±0.020 0.2552±0.005 87.81±1.84025 0.156±0.002 1.0353±0.020 1.130±0.010 0.2826±0.004 97.21±1.98030 0.160±0.001 1.0756±0.010 1.1723±0.010 0.2929±0.002 100.82±1.050SD:	Standard	deviation,	HPMC:	Hydroxypropyl	methylcelluloseTable 1: Composition for preparation of placebo filmFormulationComponent HPMC E5 (%w/v)Propylene glycol (mL)PEG 400 (mL)F1 1.5 0.1 -F2 1.5 0.2 -F3 2.5 0.1 -F4 2.5 0.2 -F5 1.5 - 0.2F6 2.5 - 0.1F7 2.5 - 0.2F8 1.5 - 0.1HPMC: Hydroxypropyl methylcellulose, PEG 400: Polyethylene glycol 40011 Gupta et al.Asian J Pharm Clin Res, Vol 11, Special issue 2, 2018, 8-11REFERENCES1. Steiner D, Finke JH, Kwade A. Redispersion of nanoparticle-loaded orodispersible films: Preservation of particle fineness. Chem Ing Tech 2017;89:1034-40.2. Parmar D, Patel U, Bhimani B, Tripathi A, Daslaniya D, Patel G. Orally fast dissolving films as dominant dosage form for quick release. Int J Pharm Res BioSci 2012;1:27-41.3. Visser JC, Woerdenbag HJ, Crediet S, Gerrits E, Lesschen MA, Hinrichs WL, et al. Orodispersible films in individualized pharmacotherapy: The development of a formulation for pharmacy preparations. Int J Pharm 2015;478:155-63.4. Borges AF, Silva C, Coelho JF, Simões S. Oral films: Current status and future perspectives: I - Galenical development and quality attributes. J Control Release 2015;206:1-19.5. Priyanka P, Rikisha L, Mayur C, Ujjaval S. Development and optimization of fast dissolving or dispersible film of baclofen using 32 central composite designs. Int J Pharm Sci Res 2014;5:5539-47.6. Arya A, Chandra A, Sharma V, Pathak K. 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A new horizon into the pathobiology, etiology and treatment of migraine. Med Hypotheses 2011;77:147-51.15. Antonaci F, Natascia G, Shizheng W, Ennio P, Alfredo C. Recent advances in migraine therapy. Springerplus 2016;5:637.16. Tayel SA, El Nabarawi MA, Amin MM, Abou Ghaly MH. Sumatriptan succinate sublingual fast dissolving thin films: Formulation and in vitro/in vivo evaluation. Pharm Dev Technol 2016;21:328-37.17. Longmore J, Shaw D, Smith D, Hopkins R, McAllister G, Pickard JD, et al. Differential distribution of 5-HT1D and 5-HT1B-immunoreactivity within the human trigemino-cerebrovascular system: Implications for the discovery of new antimigraine drugs. Cephalalgia 1997;17:833-42.18. Reuter U, Chiarugi A, Bolay H, Moskowitz MA. Nuclear factor-kappaB as a molecular target for migraine therapy. Ann Neurol 2003;51:507-16.19. Chonkar AD, Rao JV, Managuli RS, Mutalik S, Dengale S, Jain P, et al. Development of fast dissolving oral films containing lercanidipine HCl nanoparticles in semi crystalline polymeric matrix for enhanced dissolution and ex vivo permeation. Eur J Pharm Biopharm 2016;103:179-91.20. Sharma R, Kamboj S, Singh G, Rana V. Development of aprepitant loaded orally disintegrating films for enhanced pharmacokinetic performance. Eur J Pharm Sci 2016;84:55-69.21. Mishra R, Amin A. Formulation and characterization of rapidly dissolving films of cetirizine hydrochloride using pullulan as a film forming agent. Indian J Pharm Educ Res 2011;45:71-7.22. Saxena PR, De Vries P, Villalón CM. 5-HT1-like receptors: A time to bid goodbye. Trends Pharmacol Sci 1998;19:311-6.Table 6: In vitro drug release of the film of HPMC E5 and PEG 400 (n=3)Time (min) Absorbance  (mean±SD)Conc. (μg/mL)  (mean±S.D.)Corrected conc (μg/mL)  (mean±SD)Amount of drug (mg)  (mean±SD)% drug release  (mean±SD)0 0 0 0 0 02 0.095±0.003 0.4195±0.030 0.4195±0.030 0.1048±0.007 32.74±2.3805 0.110±0.002 0.5778±0.020 0.5861±0.021 0.1465±0.005 45.74±1.71610 0.120±0.001 0.6720±0.010 0.6919±0.011 0.1729±0.002 53.99±0.87115 0.132±0.002 0.7931±0.020 0.8479±0.021 0.2065±0.005 64.26±2.02620 0.144±0.003 0.9142±0.030 0.9634±0.031 0.2408±0.008 75.18±2.49925 0.160±0.002 1.0754±0.020 1.1427±0.022 0.2856±0.005 89.17±1.74530 0.172±0.001 1.196±0.010 1.2851±0.012 0.3213±0.003 100.32±1.018SD:	Standard	deviation,	HPMC:	Hydroxypropyl	methylcellulose,	PEG	400:	Polyethylene	glycol	400

APPLICATION OF QUALITY BY DESIGN APPROACH FOR THE OPTIMIZATION OF ORODISPERSIBLE FILM FORMULATION

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APPLICATION OF QUALITY BY DESIGN APPROACH FOR THE OPTIMIZATION OF ORODISPERSIBLE FILM FORMULATION

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