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Qbd) Approach for Optimization and Characterization of Micro Emulsion Based Nasal Formulation of Antipsychotic/Antischizophrenic Drug- Aripiprazole

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Qbd) Approach for Optimization and Characterization of Micro Emulsion Based Nasal Formulation of Antipsychotic/Antischizophrenic Drug- Aripiprazole Int. J. Pharm. Investigation, 2020;10(3):286-293 Original Article Quality by Design (QbD) Approach for Optimization and Characterization of Micro emulsion based Nasal formulation of Antipsychotic/Antischizophrenic Drug- Aripiprazole Sharada L Deore1,*, Bhushan A Baviskar1, Anjali Kide1, Ashwin D Deshmukh1, Yogita B Khandare1, Ramdas B Rode2 1Government College of Pharmacy, Amravati, Maharashtra, INDIA. 2S.M.B.T. College of Pharmacy, Dhamangaon, Nashik, Maharashtra, INDIA. ABSTRACT Introduction: Present study is focused to develop micro emulsion based helped in identifying identification robust design parameters for rapid nasal formulation of poorly water soluble antipsychotic/anti-schizophrenic development of stable aripiprazole micro emulsion. The critical quality drug Aripiprazole. Materials and Methods: Different surfactants and co attributes (CQAs) like solubility and compatibility with excipients, dosage surfactants are screened by implementing pseudo ternary phase diagram. form, particle size, turbidity, drug content and drug release have greater Effect of concentrations of four independent variables- oil (X1), Surfactant impact on the stability and therapeutic performance of micro emulsion of (X2), co-surfactant (X3) and water (X4) on two dependent variables- aripiprazole. Conclusion: Aripiprazole containing intranasal micro emulsion particle size (Y1) and drug content (Y2) is studied from surface response is successfully developed by quality by design approach for understanding the critical quality attributes and microemulsion is better alternative over plots obtained by application of Box Behnken Design Experiment. conventional delivery systems. QTPP and CQA mediated risk assessment applied to ensure desirable Key words: Aripiprazole, Micro emulsion, Intranasal, QBD, QTPP, CQA. quality, safety and efficacy of developed microemulsion. Developed microemulsion evaluated for appearance, particle size, viscosity, drug Correspondence content, pH, conductivity, drug release, zeta potential, polydispersity Dr. Sharada L Deore index, nasal toxicity and stability. Results: DoE based QBD approach lead Government College of Pharmacy, Kathora Naka, Amravati-444 604, Maharashtra, development of suitable optimized batch of Aripiprazole micro emulsion INDIA. with particle size 95.2 nm, viscosity 120 cp, pH 6.0, 90%, drug content Email: [email protected] and about 87.33% nasal permeability release within 4 hr. Risk assessment DOI: 10.5330/ijpi.2020.3.52 INTRODUCTION Aripiprazole is an atypical antipsychotic drug with chemical name Present work is focused on QBD approach based development of 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H) effective intranasal drug delivery system for Aripiprazole in the form of quinolinone.1 It belongs to the chemical class of benzisoxazole derivatives micro emulsion. and is indicated for the management of schizophrenia. Study revealed that Aripiprazole have high affinity towards D2, D3 - Dopamine and 5 - MATERIALS AND METHODS HT serotonin receptors.2 However, the exact root cause of Schizophrenia 7 Materials is still unclear, Aripiprazole have shown significant improvement in Positive and negative symptoms in schizophrenic patients which Gift sample of Aripirazole was provided by Alembic Pharmaceuticals, indirectly suggests that dopamine and serotonin agonists helps in Vadodara. The organic solvents, excipients and other chemicals of management of schizophrenia by restoring dopamine level in frontal analytical grade were procured from S.D Fine chemicals Pvt. Ltd. cortex region of brain.2 Based on the extremely low hydrophobicity (<1 Mumbai, India. Design of Experiment (DOE), Version 7 was used for μg/mL at room temperature) and lipophilicity, it is classified as a class IV assessment of design to study optimization. Prosim software was used compound according to Biopharmaceutical Classification System (BCS). for constructing pseudo ternary diagram. It is also found that due to poor solubility drug accumulates in body Methods by 99% binding with plasma protein.3 If the solubility of Aripiprazole is enhanced, it can reduce dose frequency as well as drug deposition; also Solubility Studies enhance bioavailability of drug at targeted site.3 To select the best oil/surfactant/co surfactant for preparation of micro Micro emulsion technique offers a promising solution for solubilisation emulsion, saturated solubility studies were carried out in different oils/ of such drugs during formulation.4 Intranasal route is one of the surfactants/co surfactants.8 Excess amount of Aripiprazole was added to advanced approaches to deliver antipsychotic or neuroprotective drug 200 mg of each oil/surfactant/co surfactant in glass vial. Mixtures were directly to brain via olfactory and trigeminal nerves through cavity solicited in solicitor for 30 min. Mixture containing vials were kept in by avoiding blood brain barrier hurdle.5 QBD is now an integral part orbital shaker for 72 hr to form homogenous mixture. Samples were of formulation development at lab as well as industrial level because centrifuged at 3000 rpm for 15 min. from supernatant liquid 0.1 ml of factorial design gives best optimized batch for pilot plant scale up.6,7 solution was pipette out and diluted with ethanol. Samples were analyzed This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms. International Journal of Pharmaceutical Investigation, Vol 10, Issue 3, Jul-Sep, 2020 286 Deore, et al.: Aripiprazole Microemulsion by QbD Approach by UV-Spectrometric at 255 nm wavelength against blank sample against distilled water as blank.9,15 Percentage transmittance indicates the (same concentration of oil without drug) and calculated solubility of homogenous nature and clarity of formulation. Aripiprazole. Globule size determination: The globule size was determined using photon correlation spectroscopy (PCS) with in-built Zetasizer). The Pseudo Ternary Phase Diagram instrument is based on the principle of dynamic light scattering (DLS). The pseudo ternary phase diagrams were developed by the water The technique measures particle diffusion due to Brownian motion and titration method.8 Aliquots of each surfactant and co surfactant mixture relates this to the size of the particles. The particle size is then calculated (Smix) were mixed with the oil at ambient temperature in a (2:1, 1:2, 1:1) from the translational diffusion coefficient using the Strokes-Einstein 16 ratio. For each phase diagram, the ratio of oil to the Smix was varied as 9:1, equation. 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, 1:9 (v/v). Water was added drop wise to each oil- S mixture under vigorous stirring. After equilibrium, the samples mix Table 1: Observed responses based on Box Behnken Design. were visually checked and determined as being clear micro emulsions. No heating was done during the preparation. Phase diagrams (Figure 1) Code Oil Surfactant Co- Water Particle Drug were constructed using prosim software. (X1 ) (X2) surfactant size Content (X3) (R1) (%) Formulation of Micro emulsion The trial batches of micro emulsion were prepared by phase titration F1 10 17 47.225 24 214 85.5 method.9 Initially required quantity of Aripiprazole was dissolved in appropriate quantity of oil. The mixture was homogenized and to it, F2 10 26 47.25 16 411 50 accurately weighed quantity of surfactant: co surfactant blends were F3 5 26 47.25 8 792 39 added in small portion with constant stirring. The blends were mixed thoroughly using magnetic stirrer and to it drop wise double distilled F4 10 24 34.5 24 130 83.33 water added with continuous stirring. F5 15 26 47.25 8 250 56.67 Optimization of Micro emulsion formulation F6 10 17 34.5 16 256 90 Optimization of micro emulsion formulation was explored by applying F7 10 17 47.5 8 300 43.33 response surface methodology and experimental design BBD (Box Behnken Design) using 3 level factorial designs.10-12 Polynomial F8 10 26 60 24 977 60 model was constructed for optimization of Aripiprazole keeping four independent and two dependent variables [Table 1] using Design Expert F9 5 17 34.05 16 95.2 95 (version 7.1, Stat-Ease Inc, Minneapolis, Minnesota) and analyzed F10 10 26 34.5 16 218 83.56 statistically by analysis of variance (ANOVA). F11 10 26 47.25 18 614 56.66 Independent variable Low level Medium level High level F12 10 26 47.25 16 227 75 Oleic acid(X1) 5 10 15 Tween 80(X2) 12 25.931 36 F13 10 35 47.25 8 442 92 Transcutol-p(X3) 24.5 47.5 73.5 F14 15 26 34.5 16 665 71 Water (X4) 8 16 24 F15 10 35 60 16 450 77.23 Dependent Variable - Y1 = Particle Size, Y2 = Drug Content F16 15 26 47.25 24 218 23.88 Further optimization of formulation was done by Design Expert software. F17 10 35 34.5 16 660 95 29 experiments were planned as per 34 factorial designs. Particle size and drug content was selected as a response for optimization. F18 5 26 47.25 24 178 77 F19 15 17 47.25 16 392 58.34 Quality Target Product Profile (QTPP) and Critical Quality Analysis (CQA) F20 10 35 47.25 24 509 50.05 Description of the target product profile for identity, dosage form, F21 15 26 60 16 302 75 strength, route of administration, appearance, content uniformity, pharmacokinetics, bioequivalence, assay etc is called as QTPP. CQAs F22 5 17 47.25 16 130 70.45 are usually defined properties like physicochemical and biological
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