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Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 74 No. 5 pp. 1513ñ1525, 2017 ISSN 0001-6837Polish Pharmaceutical Society
Limited gastric residence time has complicatedthe oral sustained drug delivery system. As themajority of the drugs are better absorbed from thestomach or the upper part of small intestine, bothprevention in complete drug release in the absorp-tion zone and reduction in the efficacy of adminis-tered dose can occur due to the rapid gastrointestinaltransit (1, 2). For a number of drugs showing limit-ed bioavailability as a result of having narrowabsorption window in the upper segment of GIT,hydrodynamically balanced system (HBS); one ofthe advancements of floating drug delivery approachpromises various applications. It helps in prolongingthe gastric residence time (GRT) and increasing thequantity of drug that reaches at its site of absorptionto a maximum level, thereby improving bioavail-ability (3).
A unique antidepressant, venlafaxine (1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl cyclo-hexanol hydrochloride) is referred to as a serotonin,norepinephrine-dopamine reuptake inhibitor (4).Venlafaxine acts as an antidepressant by inhibitingthe neuronal uptake of serotonin, norepinephrine and
to a lesser degree dopamine (5, 6). Venlafaxine has avery short steady state half-life of approximately 5 ±2 h. So in order to maintain the adequate plasma lev-els of the drug, two or three times daily administra-tion is required (7). Due to its short half-life, patientsare also directed to strictly comply with the medica-tion regimen and not to miss even a single dose, asmissing a dose can produce withdrawal symptoms(8). In this situation, such a dosage form is necessarywhich is capable of releasing the drug in sustainedmanner that will also simplify the therapeutic regi-men by avoiding the requirement to administer theformulation frequently. Fewer incidences of nauseaand dizziness have also been reported with the use ofsuch types of formulations (9). The bioavailability ofvenlafaxine is low ranging from 10-45%. Accordingto BCS, it falls under the class I since it is havinghigh solubility and high permeability. It is also freelysoluble in water (572 mg/mL) (10). These propertiesof venlafaxine together with the requirement ofreduction in its frequency of administration make itan ideal candidate for the development of sustainedrelease gastroretentive dosage form.
FORMULATION, DEVELOPMENT AND IN VITRO EVALUATION OF A NOVEL SUSTAINED RELEASE HYDRODYNAMICALLY BALANCED
GASTRORETENTIVE DOSAGE FORM FOR VENLAFAXINE HCl
AQEEL ASLAM1*, SAJID BASHIR1 and BABAR MURTAZA1
1Faculty of Pharmacy, University of Sargodha, Sargodha, Pakistan
Abstract: The present study was aimed to formulate, develop and evaluate hydrodynamically balanced systemof an antidepressant, venlafaxine hydrochloride as a single unit floating capsule by the application of Box-Behnken statistical design with 3 factors, 3 levels and 15 runs. Formulations were prepared by physical blend-ing of the drug and polymers in varying ratios. The contents of hydroxyl propylmethylcellulose K15M (A), eth-ylcellulose (B) and cellulose acetate phthalate (C) were used as independent variables whereas the dependentvariables considered were the cumulative percentage drug release at 2 h (Y1), 8 h (Y2), 12 h (Y3) and total float-ing time (Y4). Mathematical model was used to evaluate the main effects and interaction terms quantitatively.Formulation optimization was done by setting the target values for the response variables. The optimized for-mulation was observed to fulfill the requirements of an optimum controlled release floating dosage form sinceit better regulated the drug release (Y1; 4.28%, Y2; 70.83% and Y3; 80.92%) and also floated well for more than16 h. It can be concluded that the hydrodynamically balanced system of venlafaxine hydrochloride can be suc-cessfully formulated as an approach to increase the gastric residence time and hence improving its bioavail-ability.
Keywords: hydrodynamically balanced system, venlafaxine HCl, Box-Behnken statistical design, formulationoptimization
1513
* Corresponding author: e-mail: [email protected]
1514 AQEEL ASLAM et al.
Response surface methodology is extensivelyused to optimize formulations by the selection of asuitable experimental design because by using it, adeeper understanding of a process or product isobtained as well as robustness of that product can beestablished (11). Box-Behnken statistical design isan advancement from factorial designs that havebeen used in response surface modeling and opti-mization so widely (12, 13).
This study was conducted with an aim todevelop floating gastroretentive capsule formulationincorporating 150 mg venlafaxine HCl along withswellable hydrophilic polymer HPMC K15M andrelease modifiers such as EC and CAP which wouldrelease the drug in stomach and upper part of GIT ina controlled manner. Since venlafaxine has betterabsorption from these regions, gastroretention of thedosage form will improve its oral bioavailability.
MATERIALS AND METHODS
Materials
Venlafaxine HCl was received as a gift samplefrom M/s Global Pharmaceuticals (Pvt.) Ltd., plot22-23, Industrial triangle Kahuta road, Islamabad,Pakistan. HPMC K4M, HPMCK15M (hydroxylpropylmethylcellulose), EC (ethylcellulose), CAP(cellulose acetate phthalate), acetone extra pure(99%) and HCl (37% pure) were obtained fromSigma-Aldrich Laborchemikalien GmbH. D-30926Seeize. Empty hard gelatin capsule shells (size # 00)were obtained from Qaiser Scientific store, Lahore,Pakistan.
Drug-excipients interaction study and identifica-
tion
Fourier transform infrared spectroscopy (FTIR)This study was done by adopting the method
described previously (14). An infrared spectrumof pure drug, each excipient and physical mixtureof optimized formulation was recorded usingFTIR spectrophotometer (IR Prestige 21, Shima-dzu). The scanning range was 4000-500 cm-1 andthe IR spectra of samples were obtained usingKBr disc method. To detect any chemical interac-tion, any alteration in the spectrum pattern of drugdue to presence of polymers was investigated.
UV spectroscopy (determination of λλmax)As described by Pawar HA and Dhavale R
(14), the UV spectrum of venlafaxine HCl solution(concentration; 3 µg/mL) in 0.1 M HCl (pH 1.2) wasrecorded in the range of 200-400 nm on doublebeam UV-visible spectrophotometer (UV 1700Shimadzu). The spectrum and wavelength of maxi-mum absorption were recorded.
Preparation of standard curve
For this purpose, procedure used by (14) wasused with some modifications. The absorbance ofvenlafaxine HCl solutions (concentration; 3, 6, 9,12, 15, 18, 21, 24, 27, 30 and 33 µg/mL) was meas-ured at 225 nm against blank i.e., 0.1 M HCl on dou-ble beam UV-visible spectrophotometer (UV 1700Shimadzu). The coefficient of correlation and equa-tion for the straight line were also determined.
Table 1. Independent variables and their levels in Box-Behnken statistical design.
Level (mg per capsule)
Parameter Low Middle High
Amount of HPMC K15M (A) -1 (200) 0 (250) +1 (300)
Amount of EC (B) -1 (50) 0 (100) +1 (150)
Amount of CAP (C) -1 (20) 0 (40) +1 (60)
Table 2. Composition of different formulations as per design.
Ingredients (mg)
F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 F13 F14 F15
Venlafaxine hydrochloride
150 150 150 150 150 150 150 150 150 150 150 150 150 150 150
HPMC K15M 300 200 300 200 250 250 250 300 200 200 250 250 250 250 300
EC 100 50 100 150 150 150 100 50 100 100 50 100 100 50 150CAP 60 40 20 40 60 20 40 40 60 20 20 40 40 60 40
Formulation, development and in vitro evaluation of a novel... 1515
Box-Behnken statistical design
One of the widely used response surfacedesigns, a Box-Behnken statistical design with 3factors, 3 levels, and 15 runs with triplicate centerpointswas employed for the formulation of hydrody-namically balanced system of venlafaxine HCl.Formulation design, optimization and other investi-gations were done using Statgraphics CenturionXVI software from Stat-Point Technologies, USA,version 15.2.0 (64 bit). The independent variables orthe factors were the amount of HPMC K15M (A),EC (B) and CAP (C). Levels of these factors wereset in the formulation design on the basis of theresults of preliminary study and were coded as -1, 0,and +1 as shown in Table 1. The responses selectedwere the cumulative percentagedrug release at 2 h(Y1), 8 h (Y2) and 12 h (Y3) and the total floatingtime (Y4). Formulation optimization was done bysetting targets for these response variables.
Preparation of capsules
Preparation of EC granulesFirstly, EC granules were prepared by
weighing 50 mg of EC and then dissolving it in 1mL of acetone. Then, this solution was granulatedwith already weighed drug content. After this, thegranules were air dried, passed through ASTM #25 mesh and finally the granules equivalent to150 mg of venlafaxine HCl were weighed sepa-rately. Similar procedure was adopted for prepar-ing EC granules containing 100 mg and 150 mg ofEC.
Filling of capsulesBy the use of low density floating polymer
such as HPMC K15M and release modifying agentssuch as EC and CAP, single unit floating capsules ofvenlafaxine HCl were formulated that wouldachieve a density lower than the gastric fluids afteradministration and hence would float. The composi-tion of designed 15 formulations has been listed inTable 2. EC granules equivalent to one hundred andfifty milligrams of venlafaxine HCl and differentquantities of polymers were weighed accurately andblended together for 10 min manually. Finally, thegranules and polymer blend was filled into theempty hard gelatin capsule shells of size # 00 man-ually.
In vitro analysis
Evaluation of in vitro drug releaseFor this purpose, method described by (14) was
used with some modification. USP type II (paddle)apparatus (Pharma test) was used to perform drug
release studies in vitro. The operating speed for thepaddle was 50 rpm and the apparatus was main-tained at temperature 37 ± 5OC. A single HBS cap-sule was transferred into dissolution vessel contain-ing 900 mL of 0.1 M HCl (pH 1.2) as the dissolutionmedium. Then from the dissolution vessel, 5 mL ofaliquots was removed at specified time intervalssuch as after 1, 2 (Y1), 3, 4, 5, 6, 7, 8 (Y2), 9, 10, 11and 12 h (Y3). The removed portion was replacedwith equivalent volume of fresh dissolution mediummaintained at the same temperature. The collecteddissolution samples were filtered using Whatmanísfilter paper and then after making suitable dilution(i.e., 1 mL of filtrate was taken and diluted with 0.1M HCl, pH 1.2 to make the final volume 5 mL),these were used to determine released venlafaxineHCl concentrations at 225 nm by using a doublebeam UV-visible spectrophotometer (UV 1700Shimadzu).
Evaluation of in vitro floating propertiesThe in vitro floating properties of HBS capsules
were determined visually. The capsules wereimmersed in 900 mL of 0.1 M HCl (pH 1.2) in USPtype II apparatus (Pharma test). The operating speedfor the paddle was 50 rpm and the apparatus wasmaintained at temperature 37 ± 5OC. The time requiredfor the capsules to rise to the surface was taken asfloating lag time and the time for which the capsulesconstantly remained buoyant on the surface of themedium was taken as the total floating time (Y4).
Drug release kinetics
The kinetic analysis of in vitro release data ofvenlafaxine HCl from different HBS capsules wasdone by fitting it into various mathematical modelssuch as zero order, first order, Higuchi, Hixson andCrowell powder dissolution, and KorsmeyerñPep-pas model. By calculating the r2 values, the fitness ofthe data was determined (15). This was done byusing excel solver add-in (16).
Zero-order model
It describes the systems where the drugrelease rate is independent of concentration of thedissolved substance (17).
F = Ko t (1)where, the fraction of drug that has been released intime t is represented by F, and Ko is representing thezero-order release constant and t is time in h.
First-order model
It suggests that the drug release rate dependson its concentration (18).
1516 AQEEL ASLAM et al.
lnF = K1stt (2)where, the fraction of drug that has been released intime t is represented by F, and K1st is representingthe first-order release constant and t is time in h.
Higuchi model
It is a square root model used for describing therelease of drugs incorporated into semisolid andsolid matrices developed by Higuchi et al. (19). Ithas been shown in the equation given below,
F = KH√t (3)where, F represents the fraction of drug released intime t, and KH is the Higuchi dissolution constantand t is time in h.
Hixson and Crowell powder dissolution model
This model developed by Hixson and Crowellis represented by the following equation (20),
F = 100 (1 ñ (1 ñ KHCt)3) (4)where, F represents the fraction of drug released intime t, and KHC is the dissolution constant and t istime in h.
KorsmeyerñPeppas model
They developed a simple mathematical model,relating exponentially the drug release from a poly-meric system to the elapsed time (t) (21).
F = KKPtn (5)where, F represents the fraction of drug released intime t, KKP is the rate (kinetic) constant incorporat-
Figure 1. FTIR of venlafaxine
Figure 2. FTIR of the physical mixture of optimized formulation
Formulation, development and in vitro evaluation of a novel... 1517
Figure 3. UV spectrum of venlafaxine hydrochloride in 0.1 M HCl
Figure 4. Calibration curve of venlafaxine hydrochloride in 0.1 M HCl
ing the properties of macromolecular polymeric sys-tem and drug, n is the diffusional (release) exponent,this indicates the drug release mechanism and t istime in h. The value of n is determined by linearregression of log F vs. log t. For a capsule, a cylindri-cal geometry is considered for the determination ofvalues of n for all these HBS venlafaxine capsules. Ifit is 0.45, in indicates Fickian diffusion. If it is greaterthan 0.45 but less than 0.89, it indicates anomalous ornon-Fickian diffusion and if it is equal to or greaterthan 0.89, it shows case-II transport (22).
RESULTS AND DISCUSSION
Drug-excipients interaction study and identifica-
tion
Fourier transform infrared spectroscopy (FTIR)
A slight variation was observed in the charac-teristic bands of FTIR spectrum of venlafaxine HClafter doing pre-formulation studies revealing no
chemical interaction. These spectra have been givenin Figures 1 and 2.
UV spectroscopy (determination of λλmax)
The UV spectrum of venlafaxine HCl showedthat the wavelength of maximum absorbance wasobtained at 225 nm. The UV spectrum has beenshown in Figure 3.
Calibration curve of venlafaxine
The calibration curve was found to be linear inthe range of 3-33 µg/mL and straight line equationwas obtained having the correlation coefficientvalue of 0.9935. The calibration data of Venlafaxinehas been shown in Table 3 and the calibration curvehas been shown in Figure 4.
Formulation development
Initially, HPMC K4M was evaluated for itsfloating characteristics but satisfactory results were
1518 AQEEL ASLAM et al.
Figure 5. (A-D). Main effects plot for Y1-Y4, respectively. Where HPMC: hydroxypropylmethyl cellulose, EC: ethyl cellulose and CAP:cellulose acetate phthalate
A
B
C
D
Formulation, development and in vitro evaluation of a novel... 1519
not obtained. Then, another grade of HPMC i.e.,HPMC K15M was examined and as a result ofobtaining desired results, was chosen as a low den-sity floating polymer. After the application of Box-Behnken statistical design, fifteen formulationswere prepared and then evaluated for four respons-es such as Y1, Y2, Y3 and Y4. In vitro drug releaseand buoyancy study revealed that values ofresponses for these fifteen formulations variedmarkedly indicating strong relationship betweenresponses and the factors as shown in Table 4. The
range of response Y1 was from 32.45% in F5 to43.32% in F11. Response Y2 ranged from 70.71%in F15 to a maximum of 90.29% in F2. Similarly,another response Y3 was in the range of 81.18% inF15 to 99.25% in F2 and Y4 was ranging from 10 hin F2 to 16 h in F1.
In vitro drug release
It has been observed that all designed formula-tions showed high values of Y1. Such a high releasecould be due to the probable reason that the gel layerformed by HPMC K15M that is effective in control-ling drug release is not generated immediately. Aslong as the gel barrier is being formed, there is higherosion rate and subsequent high drug release ini-tially (23-25). Then, as the hydration of polymeroccurs, the drug release slows down. So, in case ofY1, amount of HPMC K15M proved to be insignifi-cant (p > 0.05). When ANOVA was performed at95% confidence interval to estimate the significanceof the model, the factors that were significant in con-trolling drug release at the end of 2 h were theamount of EC (p < 0.05) and the amount of CAP (p< 0.05). It was also observed that Y1 and both theamount of EC and CAP have an inverse relationshipdepicting that as the amount of EC and CAP areincreased, drug release is decreased and vice versa.For instance, F5 showed the least value of Y1
(32.45%) as it contained the maximum amount of
Table 4. Observed responses in designed fifteen HBS formulations.
ResponsesFormulations
(Y1) (Y2) (Y3) (Y4)% % % h
F1 32.53 76.35 89.29 16
F2 36.43 90.29 99.25 10
F3 39.17 75.27 88.55 14
F4 34.27 74.94 87.97 10
F5 32.45 73.53 84.23 13
F6 37.26 72.03 83.73 13
F7 35.35 78.76 89.29 14
F8 36.85 81.41 93.94 16
F9 32.95 81.08 89.88 10
F10 41.91 80.49 92.37 12
F11 43.32 83.98 98.17 13
F12 35.44 80.41 94.19 13
F13 36.18 80 91.12 14
F14 33.78 81.58 96.76 14
F15 35.19 70.71 81.18 16
Table 3. Calibration data of venlafaxine (n = 4).
Concentration (µg/mL) Absorbance
3 0.1081 ± 0.00011
6 0.2043 ± 0.0003
9 0.3062 ± 0.00023
12 0.4571 ± 0.0001
15 0.5350 ± 0.00011
18 0.6333 ± 0.00021
21 0.7362 ± 0.00026
24 0.8025 ± 0.00019
27 0.9221 ± 0.00011
30 1.1124 ± 0.00013
33 1.2050 ± 0.00018
1520 AQEEL ASLAM et al.
Figure 6. (A-D). Contour plot for Y1-Y4, respectively. Where HPMC: hydroxypropylmethyl cellulose, EC: ethyl cellulose, CAP: celluloseacetate phthalate and TFT: total floating time. The amounts of HPMC, EC and CAP are in mg. The drug release at 2h, 8 h and 12 h is in %
A
B
C
D
Formulation, development and in vitro evaluation of a novel... 1521
EC 150 mg and CAP 60 mg. F7 showed 35.35% andF12 showed 35.44% of Y1 since both were formu-lated with EC 100 mg and CAP 40 mg. On the otherhand, F11 showed the highest value of Y1 (43.32%)as the amount of EC was 50 mg and CAP 20 mgonly.
As the time passed on, the gel layer formed byHPMC K15M became effective and played animportant role in controlling drug release at the endof 8 h along with the hydrophobic nature of EC coat-ing as a result of lacking any of the hydrophilicgroups (hydroxyl or carboxylic). In case of Y2, theamount of CAP proved to be insignificant (p >0.05). While the amount of HPMC K15M and theamount of EC was statistically significant (p < 0.05)as determined after performing ANOVA at 95%confidence interval. It was also observed that Y2 andboth the amount of HPMC K15M and EC have aninverse relationship depicting that as the amount ofHPMC K15M and EC are increased, drug release isdecreased and vice versa. For instance, F15 showedthe least value of Y2 (70.71%) as it contained themaximum amount of HPMC K15M 300 mg and EC150 mg. F7, F12 and F13 showed cumulative per-centage drug release of 78.76%, 80% and 80.41%,respectively, as these were formulated with HPMCK15M 250 mg and EC 100 mg. On the other hand,F2 showed the highest value of Y2 (90.29%) as theamount of EC was 50 mg and HPMC K15M 200 mgonly.
A majority of the HBS capsules extended therelease of venlafaxine HCl for more than 12 h. Thecomplex interaction between diffusion, swelling anderosion mechanisms is known to be involved in thedrug release from these hydrophilic matrices. Thehydration of HPMC controls all of these mecha-nisms. It also forms the gel barrier through whichthe drug diffuses (23). Higher concentration of thepolymer causes greater amount of gel to be formedand subsequent increase in the diffusion path lengthfor the drug due to which drug release from the for-mulation is retarded. Increase in the polymer pro-portion also cause decrease in the growth of erosion,diffusion and swelling fronts due to the formation ofa stronger gel layer and subsequent difficult entry ofmedium into the matrix (24, 26-28).
After performing ANOVA at 95% confidenceinterval to estimate the significance of the model,the amount of both HPMC K15M and EC wasproved to be significant in controlling the cumula-tive percentage drug release at 12 h (p < 0.05) andthe amount of CAP was insignificant (p > 0.05) Itwas also observed that Y3 and both the amount ofHPMC K15M and EC have an inverse relationshipdepicting that as the amount of HPMC K15M andEC are decreased, drug release is increased and viceversa. For instance, F2 showed the highest value ofY3 (99.25%) as the amount of HPMC K15M and ECwere at low level i.e., 200 mg and 50 mg, respec-tively. F7 showed 89.29%, F13; 91.12% and F12;
Table 5. Drug release kinetics of all the fifteen formulations.
Formulation Zero-order First-order Higuchi Hixson-Crowell Korsmeyer- Peppas
code K0 r2 K1st r2 KH r2 KHC r2 KKP r2 n
F1 9.9375 0.7738 0.1850 0.9807 26.5876 0.9785 0.0510 0.9631 22.3117 0.9959 0.5939
F2 11.2722 0.8558 0.2312 0.9567 30.0153 0.9600 0.0625 0.9810 22.7053 0.9970 0.6491
F3 10.0768 0.6270 0.1946 0.9645 27.1163 0.9929 0.0531 0.9202 25.6318 0.9952 0.5303
F4 9.9651 0.6008 0.1896 0.9377 26.8184 0.9882 0.0519 0.8932 25.7072 0.9895 0.5228
F5 9.6991 0.6390 0.1799 0.9602 26.0840 0.9917 0.0496 0.9158 24.4214 0.9947 0.5354
F6 9.7210 0.4258 0.1852 0.9209 26.2980 0.9929 0.0506 0.8347 27.5323 0.9948 0.4753
F7 10.2451 0.6738 0.1991 0.9664 27.5185 0.9922 0.0543 0.9374 25.1998 0.9974 0.5473
F8 10.6100 0.7183 0.2123 0.9737 28.4545 0.9885 0.0575 0.9584 25.1693 0.9979 0.5658
F9 10.2487 0.8053 0.1952 0.9856 27.3787 0.9742 0.0536 0.9799 22.1991 0.9977 0.6122
F10 10.6930 0.5823 0.2215 0.9675 28.8144 0.9959 0.0595 0.9266 27.9898 0.9965 0.5156
F11 10.8932 0.7489 0.2220 0.9503 29.1639 0.9725 0.0598 0.9447 24.9747 0.9864 0.5831
F12 10.6158 0.7364 0.2122 0.9795 28.4528 0.9864 0.0576 0.9660 24.7768 0.9981 0.5742
F13 10.2631 0.8205 0.1946 0.9774 27.3903 0.9701 0.0534 0.9754 21.8113 0.9970 0.6218
F14 10.4168 0.8661 0.1966 0.9502 27.7045 0.9509 0.0540 0.9620 20.5308 0.9916 0.6599
F15 9.1629 0.4910 0.1640 0.9196 24.7488 0.9989 0.0455 0.8407 25.1894 0.9991 0.4905
1522 AQEEL ASLAM et al.
94.19% of Y3 as these were formulated with 250 mgof HPMC K15M and 100 mg of EC. While the leastcumulative percentage drug release was shown byF15 (81.18%) since the amount of HPMC K15Mand EC was 300 mg and 150 mg, respectively, inthat formulation.
In vitro buoyancy
A majority of the formulations floated well formore than 12 h. The increased gel strength of thepolymeric combination matrices might be the prob-able reason. The mechanism responsible to makethese capsules buoyant could be the rapid hydrationand swelling of polymeric matrices resulting in theformation of a floating mass (29). The factors thatwere found to play significant role in governing Y4
after performing ANOVA at 95% confidence inter-val, were A (p < 0.05) and AC (p < 0.05). It was alsoobserved that the matrix integrity of these HBS cap-sules was satisfactory. Main effects plots and con-
tour plots for different formulation factors have beenshown in the Figure 5 (A-D) and Figure 6 (A-D),respectively.
Drug release kinetics
Table 5 lists various kinetic models computedfor all the HBS gastroretentive formulations.Venlafaxine release data were evaluated by zero-order, first-order, and Higuchi and Hixson-Crowellmodels. Some of the formulations followed first-order release patterns because the plots of the per-cent cumulative drug release versus the square rootof time were found to be linear. Hence, the mecha-nism of drug release from these formulations wasfound to be diffusion-controlled such as F1, F9 andF13. The rest of the formulations followed Higuchimodel since the regression coefficient (r2) values areranging from 0.9509 to 0.9989, suggesting that therelease of a solid drug from a hydrophilic matrixinvolved the simultaneous penetration of the sur-
Figure 7. Kinetic evaluation of the optimized formulation: Korsmeyer-Peppas plot
Table 6. Multiple response optimization.
Response (Range observed in F1 - F15) Target value
% Cumulativerelease at the end of, Low High
(i) 2 h 32.45 43.32 minimize
(ii) 8 h 70.71 90.29 minimize
(iii) 12 h 81.18 99.25 minimize
Total floating duration (h)
10 16 maximize
Formulation, development and in vitro evaluation of a novel... 1523
rounding liquid, dissolution of the drug, and leach-ing out of the drug through interstitial channels orpores. This was further augmented when the releasedata were subjected to Korsmeyer-Peppas equationwhich is used to describe the anomalous releasebehavior from the matrix. In the present study, thevalues of n, calculated per the algorithm proposedby Peppas and Sahlin (31), ranged between 0.4753-0.6599. The values of the kinetic constant (KKP),which is a direct function of matrix solubility, werefound to increase with increases in the amount ofeither polymer (32, 21). It should be noted that K1
has much lower values when compared to K0, clear-ly indicating that the release of venlafaxine was pri-marily controlled by non-Fickian diffusion depict-ing that swelling and erosion of the HBS gastrore-tentive capsules go on to increase in association withan increase in the content of any of the polymers.
Data analysis
Mathematical relationships for the measuredresponses and the independent variables or factorswere generated with the help of softwareStatgraphics Centurion XVI and are shown inEquations 6-9. These equations represent the quan-titative effect of variables (A, B, C) and their inter-actions on the response. Coefficient with more thanone factor term and those with higher order termsrepresent interaction terms and quadratic relation-ship, respectively. A positive sign represents syner-gistic effect, while a negative sign indicates antago-nistic effect or an inverse relationship between thefactors and response (30). Correlation coefficient(r2) for the equations indicates the percentage vari-ability in model fitting for that particular variable.The adjusted r2 value is more suitable for comparingmodels with different number of independent vari-ables which can be obtained by including only sta-tistically significant (p < 0.05) coefficients in theequation. The adjusted r2 value for responses Y1, Y2,Y3 and Y4 were found to be 90.78%, 93.64%,85.02% and 86.02%, respectively, which indicategood fit.
Y1 = 62.6204 ñ 0.0293A ñ 0.0915B ñ 0.6505C + 0.0006AC + 0.0012BC+ 0.0025C2 (6)r2 = 96.7056%, r2 (adjusted) = 90.78%
Y2 = 116.078 ñ 0.1222A ñ 0.2342B + 0.1750C + 0.0005AB + 0.0001AC ñ 0.0002B2 +0.001BC-
0.0037C2 (7)r2 = 97.7292%, r2 (adjusted) = 93.64%
Y3 = 97.7071 ñ 0.1061A ñ 0.0997B + 0.1289C ñ 0.0003A2 ñ 0.0001AB + 0.0008AC + 0.0005BC ñ
0.0017C2 (8)r2 = 94.6498%, r2 (adjusted) = 85.02%
Y4 = -2.95833 + 0.1017A ñ 0.0242B ñ 0.1771C ñ 0.0002A2 + 0.001AC ñ 0.0001B2 ñ
0.0003BC ñ 0.0005C2 (9)r2 = 95.0057%, r2 (adjusted) = 86.02%
Formulation optimization and evaluation
For formulation optimization, target values forthe responses (Y1-Y4) were set on the basis of invitro drug release and buoyancy study of multipletrial formulations run in the laboratory (Table 6).Composition of the optimized formulation given bythe software using this technique known as ìmulti-ple response optimizationî is shown in Table 7.
Optimized formulation was prepared by themethod as described before. Then, it was evaluatedfor Y1, Y2, Y3 and Y4 by the method as describedbefore. Furthermore, the drug release data wereanalyzed kinetically by fitting into various mathe-matical models as described above. The results ofall these parameters have been shown in Tables 8,9 and Figure 7. The desirability was maximized bythe use of optimized formulation over the indicatedregion to 0.916206 as shown in Figure 8.
It was also observed that the optimized formu-lation fulfilled the requirements of an optimum con-trolled release dosage form since it better regulatedthe drug release at the end of 2 h (34.28%), 8 h(70.83%) and 12 h (80.92%). The validity of thedeveloped model is indicated by the point that therelease profile predicted by the software was foundto be very close to that observed experimentally(Table 8). The release profile of the optimized for-
Table 7. Composition of the optimized formulation.
Composition Amount per capsule (mg)
Venlafaxine HCl 150
Amount of HPMC K15M (A) 299.999
Amount of EC (B) 149.999
Amount of CAP (C) 59.999
Table 8. Response variables of the optimized formulation(observed and predicted).
Response variables Predicted Observed
Y1 (%) 33.2004 34.28
Y2 (%) 71.5634 70.83
Y3 (%) 81.5411 80.92
Y4 (h) 16.0417 >16
1524 AQEEL ASLAM et al.
mulation could be best expressed by Korsmeyer-Peppas equation as plots showed highest linearitywith r2 of 0.9939 (Fig. 5) and the value of n was0.483 (Table 9) concluding that it followed anom-alous transport. Optimized formulation remainedfloated for more than 16 h in vitro. Therefore; inaddition to the drug release control for an extendedduration, the optimized formulation also showed theexcellent floating potential that is the prerequisitefor prolonged gastric residence of the formulation.Furthermore, in vivo and pharmacokinetic studiesare required to be carried out.
CONCLUSION
This study examines the preparation of a hydro-dynamically balanced system containing venlafaxineHCl using the synthetic polymers HPMC K15M aslow density hydrophilic polymer, EC and CAP asrelease modifiers. A systematic study using a Box-
Behnken statistical design revealed the most suitableamount of HPMC K15M, EC and CAP in the hydro-dynamically balanced system. The optimized formu-lation fulfilled all the requirements of the target setand showed suitable values of cumulative percentagedrug release at 2 h, 8 h, 12 h and total floating time.The drug release pattern followed Korsmeyer-Peppas model with anomalous transport mechanism.The applicability of the statistical optimization tech-niques in predicting the composition of an optimizedformulation is clearly indicated by the presentresearch. It can also be concluded that the hydrody-namically balanced system of venlafaxine HCl canbe successfully formulated as an approach toincrease the gastric residence time and henceimproving its bioavailability. Indeed, this approachmight be a better alternative to the conventionaldosage form. However, clinical studies should beconducted with optimized formulation in order to co-relate the in vitro and in vivo performance.
Figure 8. Contour plot showing effect of HPMC K15M, EC and CAP on desirability factor. Where HPMC: hydroxypropylmethyl cellu-lose, EC: ethyl cellulose and CAP: cellulose acetate phthalate. The amounts of HPMC, EC and CAP are in mg
Table 9. Drug release kinetics of the optimized formulation.
No. Kinetic model Value of constant Value of r2 Value of ëní
1 Zero-order K0 = 8.181 0.4723 -
2 First-order K1st = 0.156 0.9392 -
3 Higuchi KH = 24.142 0.9930 -
4 Hixson-Crowell KHC = 0.043 0.8638 -
5 Korsmeyer-Peppas KKP = 25.007 0.9939 0.483
Formulation, development and in vitro evaluation of a novel... 1525
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Received: 19. 08. 2016