Influence of Electrolytes on Controlled Release Matrix ...abap.co.in/sites/default/files/Paper-9_12.pdf · Carbopol 940 P. The major challenge in the development of new controlled

665Current Trends in Biotechnology and PharmacyVol. 7 (2) 665-672 April 2013, ISSN 0973-8916 (Print), 2230-7303 (Online)

AbstractOral controlled matrix tablets of

Diphenhydramine HCl were formulated bydifferent hydrophilic polymers such ashydroxypropyl methylcellulose K15 M (HPMCK15 M), poly ethylene oxide WSR 301 (PEOWSR 301) and carbopol 940 P along withpharmaceutically acceptable electrolytes. Thedrug candidate selected is diphenhydramine HClwhich is widely used as first generationantihistamine possessing anticholinergic, antitussive, antiemetic and sedative properties.This is mainly administered for once a dayformulation for treating chronic allergic disordersand also for psychiatric disorders. Hencediphenhydramine HCl was formulated ascontrolled release matrix tablet formulations withseveral polymers by employing pharmaceuticallyacceptable electrolytes. Electrolytes such assodium carbonate, magnesium carbonate andcalcium carbonate were used at specificconcentration (10 mg/tablet) in various formula-tions, while the drug to polymer concentrationswere maintained at different ratios as 1:2, 1:2,1:1 respectively. In this work a new attempt wasmade for in-situ interactions between drug andelectrolytes were devised to control the releaseof highly water soluble drugs from oral hydrophilicmonolithic systems. These electrolytes wereused to monitor matrix swelling and gelproperties. The results indicated that the drugreleased at a controlled rate were due todifferential swelling rate and matrix stiffening andprovides a uniform gel layer. These findings

indicated that the swelling and gel formation inthe presence of ionisable species within thehydrophilic matrices provide an attractivealternative for controlled drug delivery from amonolithic system.

Keywords: Diphenhydramine HCl, HPMC K15M, PEO WSR 301, Carbopol 940 P, SodiumCarbonate, Magnesium Carbonate, CalciumCarbonate.

Introduction Recently numerous hydrophilic polymers

have been investigated and are currently usedin the design of complex controlled releasesystems (1-3). The polymers that are most widelyused in the design of controlled release of drugsinclude non ionic Hydroxypropyl methylcellulose(HPMC K15 M), Poly ethylene oxide’s (PEO’s),Carbopol 940 P. The major challenge in thedevelopment of new controlled release devicesis to achieve optimal drug concentration at thesite of action; liberation of drug from the devicemust be controlled as accurately as possible (4).The dissolution in a monolithic matrix for lineardrug release over a prolonged period of time isnot easily achievable and still remains achallenge. The limitation of a hydrophilic polymermay be circumvented through modification ofphysical and chemical infrastructure of thepolymeric gel system by using electrolytes.

In the present investigation, studies wereundertaken for design and development of oral

Influence of Electrolytes on Controlled Release MatrixTablets of Diphenhydramine HCl

S. Vidyadhara*, V. Umamaheswar Rao, S.Siva Prasad, M. Babu Naik and T. SravaniChebrolu Hanumaiah Institute of Pharmaceutical Sciences, Guntur, Andhra Pradesh, India.

*For Correspondence - [email protected]

Influence of Electrolytes on Controlled Release Matrix tables


controlled release drug delivery systems ofDiphenhydramine HCl by matrix diffusiontechnique. It is an ethanolamine derivative andH

1-receptor antagonist, thereby preventing the

action of histamine on the cells. It is widely usedas an anti-allergic, anti-emetic and anti-tussivein many pharmaceutical preparations. It is freelysoluble in water, HCl and 7.8 pH phosphatebuffers. DPH is readily absorbed from thegastrointestinal tract. After oral doses itundergoes extensive first pass metabolism in theliver. The mean elimination half life ofDiphenhydramine HCl is about 6-9 hours (5).Based on these physiochemical, biopharma-ceutical properties and rationale of clinicalefficacy Diphenhydramine HCl was selected asdrug candidate for developing controlled releasematrix tablet formulations (6).

In the present work, a reliable process hasbeen established for inducing in-situ reactionsbetween pharmaceutically acceptableelectrolytes and drug which influences theintragel swelling dynamics and relative physicalintegrity of the swollen matrix structure.Furthermore, that may produce heterogeneousdomains within the swollen gel boundary.

In the past, alkaline compounds (or) buffershave been included in solid oral formulations forseveral acidic drugs that undergo dissolution ratelimited absorption (7).The same principle ofaddition of buffers, osmotically active agents,surfactants (or) combinations thereof has alsobeen utilised to control the swelling of hydrophilicpolymers with different coating and inclusiontechniques(8). However more specific strategyhas been employed to apply the same principleto design a simple directly compressible,monolithic controlled release system. In generalthe application of buffers and ionisablecompounds in dosage form design hasessentially been limited to the minimisation oflocalised GIT adverse effects and the solubilitydependency of poorly soluble compounds (9).

The aim of this work was to provide andexpand on a means to design, formulate and

develop a novel oral monolithic, controlledrelease tablet dosage form of a drug that maybe tailored to provide quasi steady state drugrelease over an extended period of time (10, 11).The rationale behind the mechanism anddynamics of electrolytes induced matrix stiffeningand structural changes to the gel is the basis ofcontrolled drug release has also been elucidated.The drug candidate selected is diphenhydramineHCl which is widely used as first generationantihistamine possessing anticholinergic,antitussive, antiemetic, and sedative properties.This is mainly administered as once a dayformulation for treating chronic allergic disordersand also for psychiatric disorders. Hencediphenhydramine HCl was formulated ascontrolled release matrix tablet formulations withseveral polymers by employing pharmaceuticallyacceptable electrolytes for extending the drugrelease upto 24 hours.

Materials and Methods Diphenhydramine HCl was commerciallyprocured from Yarrow Chem Laboratories,Mumbai. Hydroxypropyl methylcellulose K15 M(HPMC K15 M) was a gift sample from DowChemical’s Asia Pvt., Ltd., Mumbai. Poly ethyleneoxide WSR 301 (PEO WSR 301), Carbopol 940P and Microcrystalline cellulose werecommercially procured from Yarrow ChemLaboratories, Mumbai. Sodium carbonate,Calcium carbonate and Magnesium carbonatewere commercially procured from Qualigens FineChemicals, Mumbai.

Evaluation of powder flow properties: Thepowder blends of diphenhydramine HCl wereevaluated for flow properties such as angle ofrepose and carr’s index to find whether the blendsare suitable for compression as matrix tabletsby direct compression process.

Preparation of matrix tablets : Diphenhy-dramine HCl controlled release matrix tabletswere prepared by direct compression method.The controlled release matrix tablet formulationsconsisted of a drug, polymer and electrolytes.The weights of all formulations were maintained

Vidyadhara et al


uniformly by using MCC as diluent. The materialswere weighed and individually passed throughsieve no: 60 and blended for 15 min in doublecone blender. The powder mixture was lubricatedwith 1% talc and compressed into tablets by usinga 10 station rotary punching machine (Minipress).To minimize processing variables, all bacthes oftablets were compressed under identicalconditions. The compositions of various matrixtablet formulations were given in Table 1.

Evaluation of physical parameters : Thephysical parameters such as hardness, friability,weight uniformity and drug content wereevaluated for the prepared matrix tablets as perthe standards of official compendium (12).

Determination of swelling Index : The swellingbehaviour of a dosage unit was measured bystudying its weight gain. The swelling index oftablets were determined by placing the tablets inthe basket of dissolution apparatus using distilledwater as dissolution medium at 37 ± 0.50C. After1, 2, 4, 6 and 8 hrs each dissolution basketcontaining tablet was withdrawn and blotted withtissue paper to remove the excess water andweighed on an analytical balance (Shimadzu, Ax120). The experiment was performed in triplicatefor each time point. Swelling index was calculatedby using the following formula (13). The swellingindex for various selected formulations ofDiphenhydramine HCl matrix tablets were givenin Table 3.

Swelling index =

tabletof Dry weight

tablet)of Dry weight tabletoft (Wet weigh −

In vitro dissolution studies: Dissolutionstudies for all the matrix tablet formulations wereperformed in a calibrated 8 station dissolutiontest apparatus (LABINDIA DS 8000), equippedwith paddles (USP apparatus II method)employing 900ml of distilled water as dissolutionmedium(14). Samples were withdrawn at regularintervals up to 16 hrs. Fresh volume of themedium was replaced with the same volume tomaintain sink conditions and constant volume

was maintained throughout the experiment.Samples withdrawn were suitably diluted withsame dissolution medium and the amount of drugreleased was estimated by ELICO double beamspectrophotometer at 221nm and subsequentlyanalyzed based on the equation, first orderconstant, Higuchi constant, and the KoresmeyerPeppas constant respectively. The following arethe equations used:

In Q =k. t 1Q = k. t 2M

t / M

” =ktn 3

Where Q in the equation 1 is cumulative percentdrug remained, while Q in the equation 2 iscumulative amount of drug released, t is therelease time and k is the constant incorporatingthe structural and geometrical characteristics ofthe release device. If the value of n =0.45 inequation 3 it indicates case I (Fickian) diffusionor square root of time kinetics, 0.45<n<0.89indicates anomalous (non Fickian, drug diffusionin the hydrated matrix and the polymer relaxation)diffusion, n=0.89 indicates case II transport andn>0.89 indicates super case II transport. Linearregression analysis was performed for all theseequations and regression coefficients (r) aredetermined.

Results and Discussion The present study was under taken fordesign and evaluation of the controlled releasematrix tablets of Diphenhydramine hydrochloridewith HPMC K15 M, PEO WSR 301 and Carbopol940 P by employing electrolytes as drug releaseretardants. All batches of tablets were producedunder similar conditions to avoid processingvariables. Before compression process thepowder blends were evaluated for flow propertiessuch as angle of repose and carr’s index. Theangle of repose values and the Carr’s indexvalues of all the powder blends were in the rangeof 13.2 - 20.20 and 9.4 - 15.1% respectively. Thevalues for all the powder blends preparedestablished good and free flowing characteristics.

The compositions of various matrix tabletswere given in Table 1.These tablets were



preliminarily evaluated for various physicalparameters such as weight uniformity, hardness,friability and drug content. All batches of tabletswith electrolytes were within the weight range of250 ± 3 mg. The hardness of all the tabletformulations was in the range of 5.5 to 6 kg/cm2.Friability loss of the tablet formulations werefound to be negligible and were in the range of0.1 to 0.2% w/w. Drug content estimated for allthe tablet formulations were highly uniform withless than 2.5% variation. Drug content was alsothe same in case of matrix tablets containingelectrolytes. All the matrix tablets were preparedunder identical conditions and were found to bestable. Thus the results of physical parametersevaluated for various matrix tablets were withinthe limits.

The in vitro dissolution studies, showedgreater inhibition of drug release rate ofDiphenhydramine from the matrix tablets. Thedissolution profiles of various matrix tablets wereshown in Figures 1-3. The dissolution parametersfor all the matrix tablets were given in Table 2.The drug release from the matrix tabletformulations were extended up to 12hrs inmajority of the formulations. By the incorporationof electrolytes into hydrophilic monolithic tabletmatrices, it was possible to reduce the releaserate of drug over an extended period of time. F1,F2 and F4 formulations containing drug andpolymer in the ratio of 1:2 retarded the drugrelease up to 12hrs. It was found that increasein the concentration of polymers results in delayin the drug release. HPMC K15M, PEO WSR301 and Carbopol 940 P are hydrophilic in natureand hence the formulations containing thesepolymers showed more swelling characteristicsand drug release was extended up to 12hrs.Formulations prepared by employing electrolyteswere found to extend the drug release over 16hrs(15).

The influence of retardation of drug releaseby various electrolytes were in the order ofSodium Carbonate > Calcium Carbonate >Magnesium Carbonate. Formulations F5, F7, F9and F10 containing HPMC K15 M and PEO WSR

301 with electrolytes extended the drug releaseupto 16 hrs. Formulations F12 and F13containing Carbopol 940 P with electrolytes havereleased the drug upto 75% in 16 hrs.

The SEM images of various matrix tabletformulations indicated that the formulations F1,F2 and F3 exhibited high swelling with wide poreson its surface. The formulations F5 and F9containing electrolytes exhibited matrix stiffeningwith narrow or least pores on the tablet matrix.The SEM images of various formulations wereshown from 4

a to 4

e. Thus the inclusion of

electrolytes with in a swollen matrix for controlling

Fig. 1. Dissolution Profiles of Diphenhydramine HClMatrix Tablets with HPMC K15M, PEO WSR301 andCarbopol 940 P as polymers.

Fig. 2. Dissolution Profiles of Diphenhydramine HClMatrix Tablets with HPMC K15 M along with VariousElectrolytes

Vidyadhara et al


the release rate of Diphenhydramine may leadto the formation of free base of Diphenhydramineand fundamental structural changes in gelboundary, thus including the texural variations inthe swollen matrix. It appears that electrolyte

induced buffer threshold within the matrix placean essential role in effective interaction with drugand textural changes. Further it may be due tohigher pKa values of electrolytes, which candisplay higher buffer threshold for maintainingsuitable pH values greater than 7.0 might exertbetter and desired control on drug release frommatrix tablets (15). The following mechanismmay prevail during the period of drug release fromthe swollen intragel structure. As the dissolutionmedium enters the periphery of the tablet, thereis a rapid electrolyte water interaction withsignificant chemical reaction through electrolytesolubilization and subsequent events that maylead to both initial suppression and laterenhancement of polymer swelling. During thisinfiltration process, the electrolyte present in thegel boundary could have been converted tochloride form (for example sodium carbonate andsodium chloride) due to which the hydrochlorideform of Diphenhydramine HCl lead to theformation of free base of Diphenhydramine .Theformation of free base might cause matrixstiffening. The passive and actively formedelectrolytes within the gel matrix would competefor water leading to dehydration of polymermolecules, thus leading to suppression of initialswelling which was seen up to 2 to 3 hours withformulations containing electrolytes. After 3 hoursthe water attracted by electrolytes in to thepolymer matrix could result in solubilizing the drugmolecules which would diffuse by penetration ofwater leading to enhancement of swelling. Theswelling index characteristics of various matrixtablets were given in Table 3. From thesealterations and mechanisms of intragel changes,it appears possibility to inhibit drug dissolutionrate. This inhibition in dissolution rate appearsto be a time- dependent phenomenon. Since asmore water enters the gel matrix layer- by- layer,the electrolytes and their by products are dilutedand any drug base may revert to its hydrochlorideform, which is subsequently released.

Conclusion This work may provide a novel and simpleapproach to formulate an oral monolithic

Fig. 4. SEM Photographs of Diphenhydramine HClmatrix tablets after dissolution for 6hrs a) F1 b) F2 c)F3 d) F5 e) F9

Fig. 3. Dissolution Profiles of Diphenhydramine HClMatrix Tablets with PEO WSR 301 and Carbopol 940P along with Various Electrolytes.



Table 1. Composition of various diphenhydramine HCl matrix tablets

Ingredients(mg/tab) F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 F13Diphenhydramine HCl 50 50 50 50 50 50 50 50 50 50 50 50 50HPMC K15 M 100 - - - 100 100 100 - - - - - -PEO WSR 301 - 100 - - - - - 100 100 100 - - -Carbopol940 P - - 50 100 - - - - - - 50 50 50Sodiumcarbonate - - - - 10 - - 10 - - 10 - -Magnesiumcarbonate - - - - - 10 - - 10 - - 10 -Calciumcarbonate - - - - - - 10 - - 10 - - 10MCC 95 95 95 145 85 85 85 85 85 85 135 135 135Talc 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5MagnesiumStearate 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5Total tabletweight (mg) 250 250 250 250 250 250 250 250 250 250 250 250 250

Table 2. Dissolution parameters of diphenhydramine HCl matrix tablet formulations

Formula Zero Order First Order Higuchi Peppas

tion Code K R2 K(hr-1) R2 K(mg.h1/2) R2 N R2

F1 6.924 0.708 0.226 0.986 13.054 0.984 0.477 0.990

F2 7.092 0.785 0.220 0.995 13.682 0.991 0.494 0.992

F3 6.769 0.883 0.168 0.984 13.559 0.992 0.574 0.993

F4 5.397 0.974 0.090 0.977 11.395 0.987 0.703 0.991

F5 5.193 0.645 0.216 0.998 11.402 0.983 0.469 0.984

F6 5.803 0.599 0.181 0.992 11.687 0.981 0.459 0.983

F7 5.174 0.643 0.176 0.980 11.274 0.992 0.452 0.996

F8 3.993 0.429 0.088 0.982 8.146 0.985 0.555 0.991

F9 4.779 0.580 0.213 0.997 10.134 0.995 0.460 0.996

F10 4.327 0.514 0.104 0.987 9.009 0.993 0.475 0.996

F11 4.408 0.803 0.084 0.983 10.351 0.989 0.673 0.987

F12 4.424 0.770 0.088 0.986 10.144 0.989 0.561 0.989

F13 4.238 0.710 0.083 0.983 9.586 0.986 0.542 0.984

Vidyadhara et al


controlled release drug delivery system designedfor delivery of Diphenhydramine HCl over anextended time period. An important feature of thissystem is the potential for generating constantdrug release. The matrix tablet formulationsprepared with polymers at drug and polymer ratio1:2 in F1, F2 and 1:1 in F4 could be suitable forextending the drug release upto 12hrs. Whereasformulations F5, F7, F9 and F10 were suitableto extend the drug release upto 16 hrs due topresence of electrolytes. Hence the formulationscan be further evaluated for In vivopharmacokinetic and pharmacodynamic studiescan be performed on a suitable animal model.Their physical parameters were within IPspecified limits.

AcknowledgementsThe authors express their gratitude to

Dow Chemical’s Asia Pvt., Ltd., Mumbai, forproviding gift samples. The authors are thankfulto the management of Chebrolu HanumaiahInstitute of Pharmaceutical Sciences, Guntur, forproviding the facilities to carry out the researchwork.

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Table 3: Swelling index of diphenhydramine HCl matrix tablets

S. No Time Percent Swelling Index

(hrs) F1 F2 F3 F5 F9

1 1 86.63 89.19 79.29 72.84 71.91

2 2 130.17 103.36 101.35 102.93 95.28

3 4 160.46 148.75 139.16 135.14 135.74

4 6 181.93 179.92 163.51 159.48 149.36

5 8 193.28 190.61 188.66 172.02 162.58



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Influence of Electrolytes on Controlled Release Matrix ...abap.co.in/sites/default/files/Paper-9_12.pdf · Carbopol 940 P. The major challenge in the development of new controlled