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7/18/2019 Journal Design Expert

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Hindawi Publishing CorporationBioMed Research InternationalVolume , Article ID ,pageshttp://dx.doi.org/.//

Research ArticleDesign Expert Supported Mathematical Optimizationand Predictability Study of Buccoadhesive Pharmaceutical

Wafers of Loratadine

Prithviraj Chakraborty,1 Surajit Dey,2Versha Parcha,3

Shiv Sankar Bhattacharya,4 and Amitava Ghosh1

Bengal College of Pharmaceutical Sciences and Research, West Bengal University of echnology, B.R.B. Sarani, Durgapur,

West Bengal , India College of Pharmacy, Roseman University of Health Sciences, Sunset Way, Henderson, NV , USA S. Bhagwan Singh PG Institute of Biomedical Sciences and Research, Balawala, Dehradun, Uttarakhand , India School of Pharmaceutical Sciences, IFM University, Lodhipur Rajput, Delhi Road (NH-), Moradabad,

Uttar Pradesh , India

Correspondence should be addressed to Prithviraj Chakraborty; [email protected]

Received April ; Accepted May

Academic Editor: Yoshinori Onuki

Copyright Prithviraj Chakraborty et al. Tis is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Objective. Te objective o this work encompasses the application o the response surace approach in the development obuccoadhesive pharmaceutical waers o Loratadine (LOR). Methods. Experiments were perormed according to a 2 actorialdesign to evaluate the effects o buccoadhesive polymer, sodiumalginate (A), and lactose monohydrateas ingredient, o hydrophilicmatrix ormer (B) on the bioadhesive orce, disintegration time, percent (%) swelling index, and time taken or % drug release(70%

). Te effect o the two independent variables on the response variables was studied by response surace plots and contourplots generated by the Design-Expert sofware. Te desirability unction was used to optimize the response variables. Results. Tecompatibility between LOR and the waer excipients was conrmed by differential scanning calorimetry, FIR spectroscopy, andX-ray diffraction (XRD) analysis. Bioadhesion orce, measured with AXi texture analyzer, showed that the waers had a goodbioadhesive property which could be advantageous or retainingthe drug intothe buccal cavity. Conclusion. Te observed responsestaken were in agreement with the experimental values, and Loratadine waers were produced with less experimental trials, and apatient compliant product was achieved with the concept o ormulation by design.

1. Introduction

In the recent times, there has been tremendous advances indrug delivery to develop newer dosage orms to improve e-cacy o drugs that are currently in the market. However,regardless o the tremendous advances in alternate routes odrug delivery, oral route remains the most avoured route oadministration o therapeutic agents in respect to low cost,ease o administration, and high level o patient compliance.Pharmaceutical oral waers are an attractive routeo adminis-tration because they dissolve or deaggregate spontaneously inthe oral cavity, resulting in a solution or suspension without

water. Effectively, it is a solid dosage orm providing theconvenience o a liquid dosage orm. Majority o the drugsprescribed to patients are conventional tablets and capsules,and less attention has been paid to patients experiencingdifficulty in swallowing (dysphagia) []. Te pharmaceuticalwaers hold potential advantages like rapid disintegration,no swallowing or chewing, no coadministration o water,accurate dosing compared to liquid products,great saety, andefficacy along with patient compliance.

Buccal mucosa, an attractive route orsystemic delivery odrugs, is relatively permeable with a rich blood supply [,].A drug can be easily applied and localized at the application


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BioMed Research International

site and can also be eliminated rom there, whenever in need[]. Buccal delivery or the transmucosal absorption o drugsinto the systemic circulation offers a number o advantagesover oral delivery, especially orthose drugs that have loworalbioavailability and/or those drugs that suffer rom extensiverst-pass metabolism in the liver.

A second-generation tricyclic H antihistaminic, Lorata-dine (LOR), is marketed or its nonsedating properties. Terole o these classes o drug is to prevent and/or suppressthe action o histamine, mediated by allergen in the noseand conjunctivae, thereby eliminating symptoms, that is,itching, congestion, rhinorrhoea, tearing, and sneezing [].Earlier reports had revealed that ormulation o Loratadineas a medicated chewing gum results in an almost threeoldincrease in relative bioavailability. Tis is due to the actthat approximately % o the absorbed Loratadine wasabsorbed via the oral mucosa and thereby bypassing rst-pass metabolism []. Hence, it is an attempt to preparepharmaceuticalwaers o Loratadine with an aim to lessen thelag time and enhance the onset o action.

In the development o a dosage orm, a crucial issueis to design an optimized pharmaceutical ormulation in ashort time period with marginal trials. Due to the compli-cation in the development o pharmaceutical ormulations,some computer-based optimization techniques based onresponse surace methodology (RSM) representing the useo appropriateexperimentaldesigns and applyingpolynomialequation have been widely used [,].

Te aim o RSM is to discover the optimum operatingconditions or a given system or the way in which a particularresponse is modied by a set o variables over some specicregions o interest.

Factorial designs, dealing with actors in all possiblecombinations, are considered to be the most efficient inestimating the inuence o individual variables and theirinteractions using nominal experiments []. Te applicabilityo actorial design in the development o pharmaceuticalormulation has helped in understanding the link betweenthe independent variablesand the responsesto them [].Teindependent variables are manageable, whereas responsesare dependent. Tis supports the process o optimization byrendering an empirical model equation or the response as aunction o the different variables. Te technique needs min-imum experimentation and time, thus establishing ar morecost-effective ormulation than the conventional methods oormulating dosage orm.

Te current study aims at developing and optimizing aast-dissolving pharmaceutical waer containing Loratadine,utilizing a computer aided optimization technique. Factorial actor interaction model was employed to investigate theeffect o sodium alginate (sodium salt o alginic acid) as a bio-adhesive polymer and lactose monohydrate as an ingredient(ller) o hydrophilic matrix base [] or ormulating thewaer which will also impart a pleasant mouth ll. Tis is dueto the act that the two important variables, that is, bioad-hesiveness imparted by the incorporation o a bioadhesivepolymer and texture o waer dosage orm due to the ller,shall contribute effect on the nature and perormance o thebioadhesive pharmaceutical waers.

: Factor combination as per actorial design.

rial number Coded actor levels

Factor Factor

. 1.000

1.000 1.000

. . . .

. 1.000

1.000 .

. .

1.000 .

. .

ranslation o coded levels in actual units

Coded levels 1.000 . .

1: Sodium alginate (% w/v) . .

2: Lactose monohydrate (% w/v) .

2. Experimental

.. Materials and Method. Loratadine (LOR), hydroxy pro-pyl cellulose (HPC) (Klucel), and saccharine sodium wereprocured rom Yarrow Chem Mumbai, India; sodium algi-nate, lactose monohydrate, polyethylene glycol wereobtained rom Merck, India; sorbitol (Liquid %) wasprocured rom CDH, India; glycerol was obtained rom LobaChemie, Mumbai, India. All the other chemicals and solventsused were o AR grade.

.. Experimental Design. A 2 actorial designwas employed

where the amount o two carriers (actors) were varied atthree levels as hypothesized by the design.

Te amount o sodium alginate as a bioadhesive polymer() and lactose monohydrate () were selected as actorsand studied at three levels []. ablesummarizes the nineexperimental runs studied, their actor combinations, andthe translation o the coded level to the experimental unitsemployed during the study. Bioadhesive orce (

1), % swelling

index (2), disintegration time (3), and time taken or therelease o % o drug (

70%or

4) were taken as the response

variables.

.. Preparation of Bioadhesive Pharmaceutical Wafers of Lo-

ratadine. Te solvent casting method is undoubtedly themost widely used manuacturing process or making orodis-persible/quick dissolving thin lms or waers as depictedin the literature []. For the preparation o pharmaceuticalwaers using solvent casting method, the base lm ormingpolymer (% w/v o HPC) was mixed with the requiredamount o sodium alginate as per the experimental designand kept or overnight soaking in distilled water containinga constant proportion o propylene glycol, glycerine, andsorbitol as plasticizers. A calculated amount o LOR dissolvedin aliquot o ethanol was added in the vortex o the vigorouslystirred suspension o the plasticized aqueous polymeric gel.Lactose monohydrate was added in the suspension with


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: Composition o the casting solution as per experimentaldesign to prepare waer ormulation FNA (trial number ).

Ingredients Code: FNA

Na Alginate % w/v

HPC % w/v

PG .% w/v

Glycerin .% w/v

Saccharine Na .%w/v

Ethanol % v/v

Sorbitol .% w/v

Lactose monohydrate

Peppermint .% w/v

Loratadine .% w/v

Water (q.s)

continuous stirring ollowed by mixing saccharine sodium(sweetener) and peppermint. Te stirring process o the total

polymeric suspension was continued or hrs, and mL othe solution was casted in polypropylene petri plates (PolylabIndustries Pvt., Ltd., India) and kept overnight to removethe entrapped air bubbles. Te suspension was dried at C,and waers were cut with in-house abricated hollow punch(dia. . cm) and kept in desiccators, maintained relativehumidity (60 5%) until urther analysis []. Te thicknesso each waer was measured using a micrometer (Mitutoyo,okyo, Japan) at ve locations (centre and our corners),and the mean thickness was calculated. Samples with airbubble, nicks, or tears were excluded rom analysis. All the experimentalbatches weredesignated as FNAwith numericalsuffix rom to in accordance with the experimental design

elaborated in ables and. Te composition o the waerscasting solution or ormulation coded as FNA was detailedin able.

.. Evaluation of Buccoadhesive Pharmaceutical Wafers

... Swelling Index Study [, ]. Tree waers (surace area:

. cm2) were testedor each ormulation. Initial diameter othe waers was recorded and kept them on the surace o anagar plate (% m/v) maintained at C. Measurement o thediameter o the swollen patch was done at h. Radial swellingwas calculated rom the ollowing equation:

(%)= 100, ()

where

(%) is the percent swelling obtained by the diametermethod,is the diameter o the swollen waer afer time ,andis the original waer diameter at time zero.

... Disintegration Study []. Te waer size required or

dose delivery (. cm2) was placed on a glass petri dishcontaining mL o distilled water. Te time required orthe waer to break was noted asin vitrodisintegration time.All experimentation was done in triplicate. Te disintegra-tion process was visualized with optical scanning electronic

microscope (RLMSCOPE, model number SM, BikashScientic Instruments, WB, India). Te photographs weregiven in Figure.

... Surface pH Measurement. Surace pH o thewaers wasmeasured according to the method described elsewhere [,

]. Te waers were lef to swell or min on the surace oan agar plate. Te surace pH was measured by means o a pHpaper placed on the surace o the swollen waer. Te mean othree readings was recorded.

.. Investigation of Drug-Excipient Interactions

... AR-FIR Spectroscopy of Prepared Wafers. Attenuatedtotal reectance Fourier transormed inrared spectroscopy(AR-FIR) o blank waer, LOR, and drug-loaded waerormulations (FNA) was recorded on a Bruker-ALPHA FIRspectrophotometer with Opus sofware. Te AR-FIRspectra o LOR, blank waer, and drug-loaded waer ormu-

lation (FNA ) were given in Figure.

... Differential Scanning Calorimetry. Termal propertieso blank waer (without drug), LOR, and drug-loaded waer(FNA ) were characterized using thermal analyser (PerkinElmer, USA, ModelJADE DSC). Nitrogen at the rate o mL/min wasused as purge gas and at a varied temperaturerange o C to C at heating rate o C/min undera nitrogen atmosphere. Calibration or the temperature andheat ow was carried out using a pure alumina as internalstandard at the same heating rate o the experiments. TeDSC thermograms o LOR, blank waer, and drug-loadedwaer ormulation (FNA ) were shown in Figure.

... X-Ray Diffraction (XRD) Study of Prepared Wafers.Powder XRD pattern o LOR, blank waer, and drug-loadedwaers was recorded to gain inormation about the state odrug in the waersusingdiffractometric system(Rigaku MakeUltima-III, Japan) at . mA and KV over the range 2 = 5

to at rate o2 = 5/min. Te X-ray diffractogram oLOR, blank waer, and drug-loaded ormulation (FNA ) wasshown in Figure.

.. In Vitro Measurement of Buccoadhesion [,]. Teinvitro bioadhesion properties o the pharmaceutical waerswere assessed on bovine buccal mucosa as a model mem-

brane, using a AXi texture analyzer. Te buccal mucosaltissue was obtained rom a local slaughter house, cleaned,washed, and stored atC. Preserved buccal mucosa washydrated with simulated saliva solution and allowed to reachnormal room temperature (C) beore commencement othe experiment, and it was tied to the lower probe o theassembly. Te waer was attached to the upper probe othe assembly using double-sided adhesive. Te upper probemoves towards the lower probe with test speed . mm/secandposttestspeed mm/sec. Te waer was allowed to adhereto the bovine buccal mucosa membrane with applied orceg, return distance mm. Te experiment was carried outat room temperature (C). Te resultant orce time plot o


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: Response parameter or Loratadine-loaded buccoadhesive pharmaceutical waers prepared as per actorial design.

Formulation code Formulation composition Bioadhesive orce Disintegration time % Swelling

70%(4)Sodium alginate

(% w/v)Lactose monohydrate

(% w/v) (

1) (gm) (

2) (min) index (

3) (sec)

FNA (0,1) . . . . .

FNA (0,0) . . . . . FNA (0,+1) . . . . .

FNA (+1,1) . . . .

FNA (+1, 0) . . . .

FNA (+1,+1) . . . . .

FNA (1,1) . . . . .

FNA (1, 0) . . . . .

FNA (1,+1) . . . . .

F : Scanning electronic microscopic photographs (X) o the waer disintegration process at different time intervals.

100

90

80

70

60

50

40

30

20

3500 3000 2500 2000 1500 1000 500

Wavenumber (cm1)

Transmittance

(%)

D:/LOR.0 LOR Instrument type and/or accessory 10/05/2012

D:/FNA BLANK.0 FNA BLANK

D:/FNA.0 FNA

Instrument type and/or accessory 10/05/2012

10/05/2012Instrument type and/or accessory

1657.75

1452.99

1414.1

1262.55

1030.11

1657.75

45.

1414.1

262.

1030.11

F : FIR spectrum o LOR, blank waer, and drug-loaded waer ormulation (FNA ).


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0

10

20

30

40

50

60

70

80

90

100.6

33.1840 60 80 100 120 140 160 180 200 211.6

Temperature (C)

FNA blank

LOR-API

FNA

8.788

Heatflowe

ndo

down

(mW)

F : DSC thermograms o LOR, blank waer (FNA blank), and drug-loaded waer ormulation (FNA ).

10 20 30 40 50

2 (deg)

0

0

250500750

10001250

10 20 30 40 502 (deg)

10 20 30 40 502 (deg)

500

1000

1500

0

500

1000

1500

Drug loaded waer

Blank waer

Loratadine

F : X-Ray powder diffraction pattern o Loratadine, blankwaer, and drug-loaded waer ormulation (FNA ).

a pharmaceutical waer ormulation (FNA ) was shown inFigure.

.. In Vitro Release Study [, , ]. Te in vitro drug releaseo the waers was determined using a paddle type dissolutionapparatus (Excel Enterprises, Kolkata, India). In order tomimic thein vivo adhesion and to prevent the waers romoating, each waer was xed to a rectangular glass slab andplaced at the bottom o the dissolution vessel prior to startingthe dissolution test. Te dissolution medium was mL osimulated salivary uid. Te rotation speed was rpm atC .C. Te drug release was analysed spectrophoto-metrically at nm.Every s, mL samples were manuallywithdrawn, ltered through a .-m membrane lter,and analysed by UV-VIS spectroscopy (Termo Scientic

100

50

0

50

100

150

0 2Time (s)F

orce

(g)

F

F : Representative graph o the in vitro bioadhesion test (FNA).

UV). Te withdrawn amount o dissolution medium wascalculated. Te measurement was made in triplicate with thestandard deviation as a measure o variation.

.. Optimization Data Analysis [,]. Various RSM com-putations or the current optimization study were perormedemploying Design-Expert sofware (rial version ..., Stat-Ease Inc., Minneapolis, MN, USA). Statistical second-ordermodel including interaction and polynomial terms was gen-erated or all the response variables. Te general orm o themodel is represented as in the ollowing:

= 0+

1 +

2 +

3 +

42 +

52

+ 62 + 7

2 + 822,

()

where 0

, the intercept, is the arithmetic average o allquantitative outcomes o nine runs,1 to 8are the coefficientcomputed rom the observed experimental values o,and and are the coded levels o the independent variable(s). Tetermsand2 and2 are the interaction and polynomialterms, respectively. Te main effects (and) postulate theaverage result o changing one actor at a time rom its lowto high value. Te interaction term () shows how theresponse changes when two actors are changed accordingly.

Te polynomial terms (2 and2) symbolize nonlinearity.


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: Characteristics o Loratadine-loaded buccoadhesive phar-maceutical waers.

Formulation code Tickness Folding endurance Surace pH

FNA 0.332 0.011 6.7 0.01

FNA 0.324 0.024 6.7 0.02

FNA 0.352 0.020 6.8 0.01

FNA 0.322 0.029 6.85 0.01

zFNA 0.338 0.033 6.86 0.01

FNA 0.556 0.021 6.8 0.02

FNA 0.200 0.017 6.8 0.01

FNA 0.280 0.014 6.8 0.01

FNA 0.352 0.027 6.7 0.01

Te polynomial equation was used to draw conclusion aferconsidering the intensity o coefficient and the mathematicalsign it carries, that is, positive or negative. A positive signsignies synergesis. Statistical validity o the polynomials wasestablished on the basis o ANOVA provided in the Design-Expert sofware. Level o signicance was considered at

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