Author(s): Amit Gupta, Rashmi Dahima


DOI: 10.52711/0974-360X.2023.00588   

Address: Amit Gupta, Rashmi Dahima
School of Pharmacy, Devi Ahilya Vishwavidyalaya, Takshshila Campus, Ring Road, Indore - 452001, India.
*Corresponding Author

Published In:   Volume - 16,      Issue - 8,     Year - 2023

Pazopanib Hydrochloride is a tyrosine protein kinase inhibitor molecule approved by USFDA and European agencies for the treatment of renal cell carcinoma (RCC) patients and other renal malignancies, but it has very poor aqueous solubility. Therefore, it is essential need to improve the solubility and in vitro dispersion or release characteristics. The purpose of this study was to investigate the Pazopanib hydrochloride drug solubility in various vehicles and screening of suitable solubilizers for the preparation of self-emulsifying lipid-based drug delivery systems (SE-LBDDS) of a poorly water-soluble drug (BCS class II), Pazopanib HCl by using simplex lattice mixture design. Ternaryplots wereconstructed by using oil (Labrafac WL 1349l), surfactant (Labrasol), and co-surfactant (Transcutol-P), and the concentration ranges were determined by using a simplex lattice design. The composition of pazopanib HCl SEEDS was optimized through various dependent variables (responses)such as solubility (Y1), precipitation after 15 min (Y2), and, particle size (Y3).Solubility study of pazopanib HCl in different oils, surfactants, and co-surfactants was carried out by shake flask method at 37°C. Three formulation components were chosen based on the maximum solubility results inthe oil, surfactant, and co-surfactant category and included in the experimental design. The results were analyzed by model fitting using the standard least-squares method. Pazopanib HCl were shown maximum solubility i.e. 25.64±0.24mg/g, 57.84 ±2.91mg/g and, 44.61±1.51mg/g in Labrafac WL 1349 (oil), Labrasol (surfactant) and Transcutol-P (co-surfactant) respectively. Hence these chosen formulation component's concentrations were further optimized by using a simplex lattice design (SLD). Derived mathematical polynomial equations and models were exercised to evaluate the impact of formulation input variables on the output variables (responses) using JMP software. The model p-value for both the responses i.e. solubility and particle size were found less than 0.05 hence models were significant. The results of the mathematical analysis demonstrated that the formulation components have a significant impact on the studied responses. Hence simplex lattice mixture design can be used as a powerful quality design to predict the optimized SEDDS formulation.The applicability of simplex lattice design with desirability function helped optimize a SEEDS formulation of pazopanib HCl and the selected model has made it possible to identify the impact of the critical factors to optimize the required responses.

Cite this article:
Amit Gupta, Rashmi Dahima. Application of Simplex Lattice Mixture design and desirability function in the development and Optimization of SEDDS for protein kinase inhibitor-Pazopanib Hydrochloride. Research Journal of Pharmacy and Technology 2023; 16(8):3561-8. doi: 10.52711/0974-360X.2023.00588

Amit Gupta, Rashmi Dahima. Application of Simplex Lattice Mixture design and desirability function in the development and Optimization of SEDDS for protein kinase inhibitor-Pazopanib Hydrochloride. Research Journal of Pharmacy and Technology 2023; 16(8):3561-8. doi: 10.52711/0974-360X.2023.00588   Available on:

1.    Miyamoto S, Kakutani S, Sato Y, Hanashi A, Kinoshita Y, Ishikawa A. Drug review: pazopanib. Japanese Journal of Clinical Oncology. 2018; 48(6):503-13.
2.    Verheijen RB, Beijnen JH, Schellens JHM, Huitema ADR, Steeghs N. Clinical pharmacokinetics and pharmacodynamics of pazopanib: towards optimized dosing. Clinical Pharmacokinetics. 2017; 56(9):987-97.
3.    Bhargavi P, Naha A, Kannan S, Rama A. Development, evaluation and optimization of solid self emulsifying drug delivery system (s-SEDDS) of Lercanidipine hydrochloride. Research Journal of Pharmacy and Technology.2020; 13(10):4931-40.
4.    Jena D, Devi DA, Babikir MAO.A review on game-changing approach for the oral administration of lipophilic drug: SEDDS. Research Journal of Pharmacy and Technology.2021; 14(2):1142-8.
5.    Chandrakar Aet al. Review on the formulation considerations needed to produce a stable self-micro emulsifying drug delivery systems (SMEDDS). Research Journal of Pharmacy and Technology. 2017; 10(5):1563-70.
6.    Mahapatra APK, Saraswat R, Botre M, Paul B, Prasad N. Application of response surface methodology (RSM) in statistical optimization and pharmaceutical characterization of a patient compliance effervescent tablet formulation of an antiepileptic drug levetiracetam. Future Journal of Pharmaceutical Sciences. 2020; 82(6):1-14.
7.    Nawale RB, Deokate UA, Shahi SR, Lokhande P. Formulation and characterization of efavirenz nanosuspension by QbD approach. Research Journal of Pharmacy and Technology. 2017; 10(9): 2960-72.
8.    Cho HY, Kang JH, Ngo L, Tran P, Lee YB. Preparation and evaluation of solid-self-emulsifying drug delivery system containing paclitaxel for lymphatic delivery. Journal of Nanomaterials. 2016; 20:1-14.
9.    Cafaggi S, Leardi R, Parodi B, Caviglioli G, Bignardi G. An example of application of a mixture design with constraints to a pharmaceutical formulation. Chemometrics and Intelligent Laboratory Systems. 2003; 65:139-47.
10.    Kolekar YM. Understanding of DoE and its advantage in pharmaceutical development as per QbD approach. Asian Journal of Pharmacy and Technology. 2019; 09(4):271-5.DOI:10.5958/2231-5713.2019.00045.X
11.    Saxena S, Bawa S, Katare DP. Statistical and continuous manufacturing approach by design of experiment (DoE) for a robust synthetic process of a sorafenib analogue. Research Journal of Pharmacy and Technology. 2020; 13(1):1-8.DOI:10.5958/2231-5713.2020.00001.3
12.    Eriksson L, Johansson E, Wikstrom C. Mixture design- design generation, PLS analysis, and model usage. Chemometrics and Intelligent Laboratory Systems. 1998; 43:1-24.
13.    Patel A, Gohel M, Soni T. Partial least square analysis and mixture design for the study of the influence of composition variables on nanoemulsions as drug carriers. Research Journal of Pharmacy and Technology. 2014; 7(12):1446-55.
14.    Visetvichaporn V, Kim KH, Jung K, Cho YS, Kim DD. Formulation of self-microemulsifying drug delivery system (SMEDDS) by d-optimal mixture design to enhance the oral bioavailability of a new cathepsin K inhibitor (HL235). International Journal of Pharmaceutics. 2020; 573:1-9.
15.    Cho HJ, Lee DW, Marasini N, Poudel BK, Kim JH, Ramasamy T, Yoo BK, Choi HG, Yong CS, Kim JO. Optimization of self-microemulsifying drug delivery system for telmisartan using Box-Behnken design and desirability function. Journal of Pharmacy and Pharmacology. 2013; 65(10):1440-50.DOI:10.1111/jphp-12115
16.    Ekshinge VB, Garala KC. Formulation development of tramadol hydrochloride rapid-disintegrating tablets using simplex lattice design. Research Journal of Pharmacy and Technology. 2009; 2(4): 753-5.
17.    Phadke S, Kanekar T, Gumaste S, Parikh V. Application of simplex lattice design for the development of extended release tablets of model drug diclofenac sodium.  Therapeutic Delivery. 2019; 10(8):515-25.
18.    Stuchlik M, Zak S. Lipid-based vehicle for oral drug delivery. Biomedical Papers-Palacky University in Olomouc. 2001; 145(2):17-26.DOI:10.5507/BP.2001.008
19.    Pandey V, Kohli S. Lipids and surfactants: The inside story of lipid-based drug delivery systems. Critical Reviews in Therapeutic Drug Carrier Systems. 2018; 35 (2): 99-155. DOI:10.1615/CritRevTherDrugCarrierSyst.20180160710
20.    Cannon JB. Strategies to formulate lipid-based drug delivery systems. American Pharmaceutical Review. 2011; 14(4):84-92.
21.    Shah A, Desai H, Thool P, Dalrymple D, Serajuddin Abu TM. Development of self-microemulsifying drug delivery systems of poorly water soluble nutraceuticals. Drug Development and Industrial Pharmacy. 2018; 44(6): 895-901.DOI:10.1080/03639045.2017.1419365
22.    Mohanrao BM, Sundar PS, Nagsen S. Oral bioavailability enhancement of a poor water soluble drug by co-surfactant free self-emulsifying drug delivery system (SEDDS). Research Journal of Pharmacy and Technology. 2011; 4(10):1557-62.
23.    Wang S, Sun M, Ping Q. Enhancing effect of labrafac lipophile WL 1349 on oral bioavailability of hydroxysafflor yellow A in rats. International Journal of Pharmaceutics. 2008; 358:198-204.
24.    Devani MJ, Ashford M, Craig DQM. The development and characterization of triglyceride-based ‘spontaneous’ multiple emulsion. International Journal of Pharmaceutics. 2005; 300: 76-88.
25.    Dahan A, Hoffman A, The effect of lipid based formulations on the oral absorption of lipophilic drugs: the ability of in vitro lipolysis and consecutive ex vivo intestinal permeability data to predict in vivo bioavailability in rats. European Journal of Pharmaceutics and Biopharmaceutics 2007; 67:96-105.
26.    Elbardisy B, Galal S, Abdelmonsif DA, Boraie N. Intranasal tadalafil nanoemulsions: formulation, characterization and pharmacodynamic evaluation. Pharmaceutical Development and Technology. 2019; 24(9):1083-094.
27.    Ponnaganti H, Abbulu K. Enhanced dissolution of repaglinide: SMEDDS formulation and in-vitroevaluation. Research Journal of Pharmacy and Technology. 2014; 7(11):1246-52.
28.    Hu Z, Tawa R, Konishi T, Shibata N, Takada K. A novel emulsifier, labrasol, enhances gastrointestinal absorption of gentamicin. Life Sciences. 2001; 69 (24):2899-910.
29.    Caddeo C, Manconi M, Valenti D, Maccioni AM, Fadda AM, Sinico C. The role of labrasol in the enhancement of cutaneous bioavailability of minoxidil in phospholipid vesicles. Research Journal of Pharmacy and Technology. 2012; 5(12):1563-69.
30.    Cho HJ, Ku WS, Termsarasab U, Yoon I, Chung CW, Moon HT, Kim DD. Development of udenafil-loaded microemulsions for intranasal delivery: in vitro and in vivo evaluations. International Journal of Pharmaceutics. 2012; 423:153-60.
31.    Patel MR, Patel RB, Bhatt KK, Patel BG, Gaikwad RV. Paliperidone microemulsion for nose-to-brain targeted drug delivery system: pharmacodynamic and pharmacokinetic evaluation. Drug Delivery. 2014; early online:1-9.
32.    Hauss DJ. Oral lipid-based formulations. Advanced Drug Delivery Reviews. 2007;59:667-76.
33.    Pouton CW. Formulation of poorly water- soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. European Journal of Pharmaceutical scienCes. 2006; 29:278-87.
34.    Krstic M, Medarevic D, Duris J, Ibric S. Self-nanoemulsifying drug delivery systems (SNEDDS) and self- microemulsifying drug delivery systems (SMEDDS) as lipid nanocarriers for improving dissolution rate and bioavailability of poorly soluble drugs. Lipid Nanocarriers for Drug Targeting. 2018:474-508.
35.    Niamprem P, Rujivipat S, Tiyaboonchai W. Development and characterization of lutein-loaded SNEDDS for enhanced absorption in Caco-2 cells. Pharmaceutical Development and Technology. 2013; early online:1-8.
36.    Qi X, Qin J, Ma N, Chou X, Wu Z. Solid self-microemulsifying dispersible tablets of celastrol: formulation development, characterization and bioavailability evaluation. International Journal of Pharmaceutics. 2014; 472:40-7.

Recomonded Articles:

Research Journal of Pharmacy and Technology (RJPT) is an international, peer-reviewed, multidisciplinary journal.... Read more >>>

RNI: CHHENG00387/33/1/2008-TC                     
DOI: 10.5958/0974-360X 

56th percentile
Powered by  Scopus

SCImago Journal & Country Rank

Recent Articles


Not Available