effects caused by the sudden increased levels due to the IR formulations as In addition to having more stable pharmacokinetic profiles, some controlled-release formulations are associated with lower incidences of nausea than are IR formulations⁶, or in terms of the better pharmacokinetics without any loss of its efficacy when switched from IR (to be given b.i.d.) to XR Venlafaxine (given OD) in patients also the constant and slower absorption profile from XR formulation give a better choice of switching from an IR formulation.⁷ Hence an OD formulation of Venlafaxine is the suitable choice for a formulator to formulate.

Several approaches has been utilized previously to develop the sustained release formulation of Venlafaxine include Hydrogel based once daily tablets of Venlafaxine using hydroxypropyl methylcellulose (Methocel K100M),⁸ sustained release matrix tablets were also investigated utilizing hydrophobic wax matrix system composed of bees wax and carnauba wax.⁹ Again a triple layered matrix tablet was developed using xanthan gum in the intragranular and extragranular fractions of layered matrix to provide substantial water uptake and gelling resulting in sustained release profile of Venlafaxine comparable to marketed product.¹⁰

To develop an extended release formulation of VNH a freely water soluble drug having a solubility about 572 g/L¹¹ is always difficult hence it led to the development of spheroids formulation containing drug and microcrystalline cellulose protecting the drug with an insoluble coating of ethyl cellulose a release controlling polymer to produce desired therapeutic blood levels of the drug which can be matched by a dissolution profile of 24 hrs. Extended release spheroids were developed as it was thought that the commonly used hydrogel based tablet formulations are difficult to develop for such type of drugs being physically unstable and unable to attain desired sustained release kinetics.¹² It is already documented that the significant reduction in dosing frequency can be obtained by venlafaxine sustained release formulations.¹³

Due to improved technology and accessibility towards newer polymers and excipients it has become possible to develop an extended release tablet formulation of Venlafaxine but it is still a challenge to control its release rate in dissolution media. In order to prepare a stable and reliable tablet formulation of VNH present study utilizes the hydrogel based approach of chitosan and hydrophobic nature of HVO in a single dosage form by introducing layered tabletting in order to get desired release profile of Venlafaxine in distilled water as dissolution media.

MATERIALS AND METHODS:

Materials:

Venlafaxine hydrochloride provided by Alembic Ltd, Baroda, India was taken as model drug for the study to justify the need of once a day formulation. Chitosan 652 with degree of deacetylation 90% of Daksh ltd., India, was used being highly deacetylated and fine powder grade. Hydrogenated vegetable oil (Lubritab) and pregelatinized starch (Starch 1500) were provided by Sanofy Aventis India Ltd., Goa were utilized as a lipid core material for matrixing the drug and hydrophilic bulking agent respectively. HPMC (Methocel E-5) was obtained as gift samples from Colorcon Asia Pvt. Ltd., India and used for its rapid hydrating properties. Ethyl cellulose 7cps was obtained from Signet Chemicals, India was used as a lipophilic diluent for the composition. Acetic Acid Glacial AR grade from Loba Chemie was used as the granulating agent. Polyvinyl pyrollidone (PVP K-90) was used as dry binder and Magnesium stearate as lubricating agent obtained from Bayer India Ltd, India. All other solvents and reagents used in were of analytical grades.

Drug excipients compatibility studies:

Compatibility between drug and excipients was investigated by Fourier Transform Infrared Spectroscopy where the spectra were recorded for wave number from 400 to 4000 against KBr disc as blank standard using FTIR spectrometer (460 Plus, Jasco) and differential scanning calorimetry (DSC) using Mettler TA 4000 thermal analyzer in which the thermal analysis was performed in a nitrogen atmosphere at a heating rate of 10°C/min over a temperature range of 30 - 300°C employing alumina as the reference standard. Blend containing drug and excipients (all the excipients together in proposed ratio) was exposed to the elevated conditions of temperature and relative humidity (40°C ± 2°C and 75% ± 5% RH) for 1 month. Finally the IR spectra and DSC thermograms recorded were compared with that of pure drug, excipients and unexposed drug-excipients blend.

Preparation of VNH Extended release tablets:

Previously weighed amounts of all intragranular ingredients like chitosan, Ethyl cellulose, Pregelatinized starch and HPMC E-5 were mixed well and granulated with diluted Acetic acid (in 1:1.25 molar ratio of glucosamine unit of chitosan to acetic acid) and allowed to dry in a tray dryer at controlled temperature not exceeding 50° C followed by the sizing of dried granules through # 30 mesh (600µ) to yield uniform granules to which added # 60 mesh passed extragranular PVP K-90 and lubricated Magnesium stearate to get chitosan based polymeric blend to be used for barrier layers of the tablet. Desired quantities of VNH equivalent to Venlafaxine and HVO were mixed well and transferred to a beaker and exposed to temperature of about 60°C - 70°C using a heating mental while stirring continuously with mechanical stirrer till the hot mass of desired consistency obtained which then cooled and passed through # 20 (840µ) to get uniform blend to be used for the preparation of middle drug layer of the tablet. Triple layer matrix tablets then compressed using the previously prepared blends with a Cadmach single station tablet press using round flat faced punches of 13 mm diameter by precompressing different blends in order, the polymeric blend, drug blend and again polymeric blend one on other with a slight compression pressure to ensure the uniformity of layers followed by compression all together to a compression force of 4 Ton to

Table I: Composition details of different preliminary trial batches.

Sr. No.	INGREDIENTS	F 1 (mg)	F 2 (mg)	F 3 (mg)	F 4 (mg)	F 5 (mg)	F 6 (mg)	F 7 (mg)	F 8 (mg)
1	Chitosan	200	200	200	0	0	250	200	200
2	Ethyl Cellulose	0	100	100	100	0	150	120	120
3	Starch 1500	100	100	100	100	0	100	80	80
4	HPMC E-5	100	100	100	100	0	100	80	80
5	Acetic Acid	40	40	40	40	0	50	40	40
6	PVP K-90	0	25	25	25	0	30	24	24
7	Mg. Stearate	10	10	10	10	0	20	16	16
8	Venlafaxine HCl	170	170	170	170	170	170	170	170
9	HVO	0	0	100	100	100	80	80	80
Tablet Wt. (mg)		620	745	845	645	270	950	810	810
Type of Matrix Layer		Single	Single	Single	Single	Single	Single	Double	Triple

Table II: Factor levels for the experimental design for optimization trials

Factor Details			Factor Level
Code	Actual	Unit	-1	0	+1
(X₁)	Chitosan in polymeric layer	mg	200	250	300
(X₂)	HVO in drug layer	mg	60	80	100

Fig 1: Comparative DSC thermograms of drug, excipients and combination

get a final triple layered matrix tablet containing middle drug layer with upper and lower polymeric barrier layer of desired combination. The tablets prepared were evaluated for different physical and chemical parameters.

Physical evaluation:

Ten to twenty tablets from each trial batch were evaluated for various tests like uniformity of tablet weight using

analytical balance (AND, India), thickness and diameter using Vernier calliper of 0.01-mm precision (Mitutoyo, Japan,), Hardness was tested by Monsanto type tester (Campbell, Mumbai, India) and friability using a Roche-type friabilator (Electrolab, India) as described in IP 1996.¹⁴

Drug Content:

Ten tablets were powdered and the blend equivalent to 150 mg of Venlafaxine was weighed and dissolved in suitable quantity of distilled water. The solution was suitably diluted, filtered and drug content was analyzed spectrophotometrically (UV-1700, Shimadzu, Japan) at 225 nm against the standard solution of known concentration where each sample was analyzed in triplicate.

In Vitro Release Study:

Drug release studies (n = 6) were conducted for all the formulation combinations using dissolution test apparatus (Disso 2000, Lab India, India). Distilled water (900 ml) was taken as the release medium at 75 rpm and 37±0.5ºC employing USP II paddle method (Apparatus 2). Aliquots of samples were withdrawn at the specified time intervals (2, 4, 8, 12 and 20 hrs)¹⁵, filtered through whatman filter paper and after suitable dilutions analysed spectrophotometrically (UV-1700, Shimadzu, Japan) for drug content at 225 nm. An equal volume of pre-warmed (37°C) fresh medium was replaced into the dissolution medium after each sampling, to maintain the constant volume throughout the test. Time required to obtain 20%, 50% and 90% (T₂₀, T₅₀ and T₉₀ respectively) were treated as the points of desired release as obtained for the reference marketed product Venlafaxine Extended Release Capsules, Ranbaxy (Solus), when tested for the conditions described by Office of Generic Drugs, CDER¹⁵ and were set to be achieved in 2, 8 and 20 hrs respectively to justify the need of an venlafaxine OD formulation. The optimized formulation was analysed for in-vitro release in three different media having different pH like 0.1 N HCl, distilled water and pH 6.8 phosphate buffer to assess the pH independent behaviour of the formulation.

Experimental Design:

Feasibility trials were taken utilizing mainly chitosan with commonly used excipients to get a good behaving matrix composition in terms of tablet and dissolution parameters, which was kept same for all Preliminary trials while changing the weight of composition with respect to the quantity of chitosan desired, when used whether alone, in combination with lipid granules or as multilayer tablet must withstand the impact of dissolution test and at the same time retard the release of freely water soluble drug for desired period. Compositions of different preliminary trials are given in Table I.

Fig 2: Comparative FTIR Spectra of drug, excipients and combination.

Factorial Design:

Design of experiment (DOE) has been widely used in pharmaceutical field to study the effect of formulation variables and their interaction on response variable hence a factorial design to optimize the experiments on the basis of response methodology was employed.¹⁶ A good behaving and workable composition was taken as the centre point for optimization of the formulation and a 3 level factorial design was constructed to study the effect of the amount of chitosan (X₁) and the amount of HVO (X₂) on the drug release from triple layer matrix tablets of VNH. The dependent variables chosen were times required for 20% (T₂₀), 50% (T₅₀) and 90% (T₉₀) cumulative drug release. High and low levels of each factor were coded as +1 and −1, respectively, and the mean value as zero. The range of a factors were chosen in order to adequately measure its effects on the response variables which in present study were times to reach particular dissolution points in terms of % cumulative drug release as T₂₀, T₅₀ and T₉₀. Furthermore it was desired that all experiments must be practical on the equipment used. In this design 2 factors were evaluated, each at 3 levels, and experimental trials were performed at all 9 possible combinations and additionally centre point combination was repeated 3 times to ensure the precision. All other formulations and processing variables were kept invariant throughout the study. Table II summarizes the factor combinations and translation of coded levels to the experimental units and values.

Fig: 3 Contour Plots and Response Graphs for T₂₀, T₅₀ and T₉₀.

Table III: Observation for the different preliminary trials

Tablet Parameters	F 1	F 2	F 3	F 4	F 5	F 6	F 7	F 8
Weight variation (%) *	+ 1.4 to - 2.6	+ 1.3 to - 3.6	+ 2.3 to - 3.2	+ 3.5 to - 3.3	+ 3.6 to - 2.6	+ 1.8 to - 1.8	+ 3.2 to - 3.6	+ 3.1 to - 2.5
Hardness (Kg/cm²) #	3 ±0.33	4.5 ±0.35	5 ±0.74	3 ±0.59	4 ±0.60	6 ±0.27	5 ±0.86	6.5 ±0.38
Friability (%) #	0.76 ± 0.12	0.48 ± 0.26	0.35± 0.29	0.80± 0.45	0.29± 0.25	0.38± 0.47	0.58± 0.66	0.43 ± 0.47
Drug content (%)	99.2 ± 0.74	99.4 ± 0.68	98.8 ± 0.38	98.8 ± 0.66	99.4 ± 0.33	98.9 ± 0.49	100.1 ±0.52	99.6 ± 0.73
Dissolution Studies	Time in hrs to attain given % drug release
T₂₀	1	1	1	0.5	1	1	1	2
T₅₀	2	2	2	1	2	2	2	8
T₉₀	4	8	12	2	8	12	12	20
Acceptability	No	No	No	No	No	No	No	Yes

* is the mean of 10 values ± SD, # is the mean of 6 values ± SD

Table IV: Factorial design trial and its responses.

Trials	Run	Independent Variables (mg)		Dependent Variables (Hrs.)
		Chitosan	HVO	T₂₀	T₅₀	T₉₀
1	7	200	60	1	4	8
2	6	250	60	1	4	12
3	1	300	60	2	4	12
4	12	200	80	2	8	12
5	11	250	80	2	8	20
6	10	300	80	2	8	20
7	4	200	100	2	8	20
8	5	250	100	4	8	20
9	9	300	100	4	12	24
10	8	250	80	2	8	20
11	2	250	80	2	8	20
12	3	250	80	2	8	20

A 3 level factorial design Response surface methodology was performed to evaluate the observations. The experimental design provides sufficient data to fit a quadratic polynomial analysis for various dependent factors. All tests were performed for at least 95% level of significance (α=0.05), Power should be approximately 80% for the effects desired. The adequacy of the final quadratic models was examined by Fit summary, analysis of variance (ANOVA), and three-dimensional response surface graphs and contour plots drawn using Stat Ease Design Expert^® (Version 7.1.1) software.¹⁷

Data Analysis by Kinetic modelling of drug release profile:¹⁸

The dissolution profile of the optimized composition was fitted to different model equations to ascertain the kinetic modelling of drug release profile. All the mathematical models were fitted by using the SigmaPlot version 10 software1⁹ and evaluated on the basis of responses in terms of slope, regression coefficient and fit test. Various equations can be expressed in terms of Q as amount of drug, K as equation constant, 0, t and ∞ are the times corresponding to the release.

ln Q_t = ln Q₀ + Kt . . . . Eqn. 1

Q₀^1/3 - Q_t^1/3 = K_st . . . . Eqn. 2

Q = K t^1/2 . . . . Eqn. 3

(3/2) [1- (1- Q_t /Q_∞)^2/3] - (Q_t /Q_∞) = K_t . . . . Eqn. 4

Q_t /Q_∞ = Ktⁿ . . . . Eqn. 5

First order release kinetics can be described by the equation 1 where a graphic of the decimal logarithm of the released amount of drug versus time will be linear. Here the dissolution profile of a dosage form is such that of a formulation containing water-soluble drugs in porous matrices release the drug in a way that is proportional to the amount of drug remaining in its interior.

Hixon and Crowell in 1931 recognized that the particle regular area is proportional to the cubic root of its volume, derived an equation that can be described in the following manner of equation 2 where Q₀ is the initial amount of drug in the pharmaceutical dosage form, Q_t is the remaining amount of drug in the pharmaceutical dosage form at time t and K_st is a constant incorporating the surface–volume relation. This expression applies to pharmaceutical dosage form such as tablets, where the dissolution occurs in planes that are parallel to the drug surface if the tablet dimensions diminish proportionally, in such a manner that the initial geometrical form keeps constant all the time mainly applied for the lipidic matrices.

Higuchi in the equation 3 describes drug release as a diffusion process based in the Fick’s law, square root time dependent. This relation can be used to describe the drug dissolution from several types of modified release pharmaceutical dosage forms like transdermal systems and matrix tablets with water soluble drugs.

Baker–Lonsdale stated in a way of relating the left side of the equation 4 and time will be linear if the established conditions were fulfilled where the release constant k corresponds to the slope. This equation has been used to the linearization of release data from several formulations of microcapsules or microspheres.

Korsmeyer–Peppas in 1985 used the equation 5, here n value can be used to characterise different release mechanisms, concluding like for n = 0.5 follow a Fick diffusion and higher values of n i.e. between 0.5 and 1.0 for mass transfer follow a non-Fickian model or Anomalous transport. It is also necessary that release occurs in a one-dimensional way and that the system length to thickness relation should be at least 10. This model is generally used to analyze the release of pharmaceutical polymeric dosage forms, when the release mechanism is not well known or when more than one type of release phenomena could be involved.

Stability studies:²⁰

Stability studies for optimized formulations (three different batches) were performed by subjecting the samples to storage at room temperature and at accelerated conditions of temp. and relative humidity i.e. 40°C ± 2°C and 75% ± 5% RH for 3 months and the exposed samples were compared against the initial samples for drug content and dissolution profile.

RESULTS AND DISCUSSION:

DSC thermograms show good compatibility between the drug and studied excipients as shown in Fig. 1 which can be evidenced by no shift of drug peak position, onset and endset patterns which can be characterized by a sharp peak at about 210°C and Placebo with a distinguished peak of HVO at about 60°C too does not show any impact of drug and other excipients. The IR spectra also eliminate the possibility of any kind of interaction between the drug and excipients when compared as all the major stretchings due to the functional groups at 3350 cm^-1[-OH], 1513 cm ^-1 [Aromatic moiety], 1247 cm ^-1 [-OCH₃] and 1180 cm ^-1 [-N (CH₃)₂] were seen unchanged in subsequent spectra of drug alone and drug with excipients upon exposure when kept together as per Fig: 2.

Chitosan based matrix are rare to found, being insoluble in water chitosan does not produce any hydrogel system in presence of water hence acetic acid was used to form chitosan acetate thereby increasing water solubility of chitosan and producing gelling tendency which can act as release rate controlling hydrogel due to the electrovalent bond in the chitosan acetate which behave as a salt hence soluble in water because of the protonation of amino group of chitosan,²¹ the same property of chitosan has been utilized for the present investigation in the formulation of VNH extended release tablets.

From the initial preliminary trials taken as per the observations in Table III in the form of chitosan matrix tablets it was clear that a hydrophobic bulking agent (Ethyl cellulose) is required to produce the bulk and strength to the formulation as well as being water insoluble it can help to retard the release of drug in dissolution media also an extragranular dry binder (PVP K-90) is required to improve the binding thereby hardness of the tablets which is evident by the comparison of formulations F1 and F2, in further trials HVO as lipophilic material was incorporated (F3) to further retard the drug release as alone chitosan matrix could not be able to control the drug release for as long as 20 hrs as desired. Further the effect of chitosan in matrix formulation was confirmed as the formulation without chitosan (F4) even did not produce the significant release retardation also was not found to be strong enough physically. Composition containing only drug and HVO (F5) also did not work as it was not able to control the drug release even up to 12 hrs also the higher amount of HVO was avoided to eliminate any chance of instability on storage hence an increased amount of chitosan and ethyl cellulose were tried (F6) yielding a good behaving matrix composition but still not satisfactory in terms of drug dissolution rate. Further to check the possibility of getting a good dissolution profile, a bilayer matrix composition (F7) containing a chitosan matrix behaving as barrier layer and a drug layer containing HVO was tried and found to be not working as still one surface of the drug layer was exposed which was responsible for the still faster drug release from the drug layer, hence a triple layer tablet (F8) was formulated consisting of upper and lower chitosan barrier layers and a middle drug layer which behave good in terms of physical evaluation and in-vitro release profile of about 20 hrs. Physical behaviour of the triple layer tablet in dissolution media reveal that the polymeric chitosan layers behaves like barrier layers which upon swelling produce a hydrogel structure and covers the middle drug layer from which drug diffuses in controlled manner having limited exposed area. The two types of blends used in preliminary trials like the chitosan containing polymeric blend and drug containing HVO blend were analysed for various evaluation tests for granules and found to be having sufficient flow properties and compressibility characteristics.

Experimental trials were performed for all 9 possible combinations as per the factorial design described in Table II. All the batches were prepared according to the desired independent parameters and evaluated for the different dependent parameters desired to get the response and to obtain the optimized formulation which can further be evaluated completely for the various dissolution characteristics. A quadratic 3 level factorial design Response methodology was performed to evaluate the observations. Degrees of Freedom (DF) for Evaluation observed was 3 for lack of fit (LOF) and pure error, where minimum 3 DF was desired to ensures a valid test design hence the design was found to be acceptable in terms of degree of freedom. The nine formulations were designed, using various higher and lower levels of chitosan and HVO as per Table II. The preparations of each composition were tested separately for weight variation and friability and found to be within the pharmacopoeial limits apart from that the hardness was found to be between 5 to 7 kg/cm² for all the possible compositions although the thickness of the various formulations vary according the composition chosen.

A statistical model incorporating interactive and polynomial analysis was utilized to evaluate the response as per the equation 6.

Y = b₀ + b₁X₁ + b₂X₂ + b₁₂X₁X₂ + b₁₁X₁² + b₂₂X₂ ² ....Eqn. 6

Where, Y is the dependent variable, b₀ is the arithmetic mean response of the 9 + 3 runs, b₁ is the estimated coefficient for the factor X₁ and b₂ is the estimated coefficient for the factor X₂. The main effects (X₁ and X₂) represent the average result of changing one factor at a time from its low to high value. The interaction terms (X₁ X₂)

Table V: Constraints were set for Response Surface Methodology optimization

Factor	Factor type	Goal	Lower Limit	Higher Limit	Importance
Chitosan	Independent	Should be minimum	200	300	4
HVO	Independent	Should be minimum	60	100	4
T₂₀	Dependent	Should be maximum	1	4	4
T₅₀	Dependent	Targeted to 8	4	12	4
T₉₀	Dependent	Should be maximum	8	24	5

Table VI: Solution for Optimized Composition as per response methodology.

Factors	Chitosan	HVO	T₂₀	T₅₀	T₉₀	Desirability
Values	239.68	82.49	2.05701	8.00001	19.3307	0.586

Table VII: Evaluation of Optimized formulation and their results.

Evaluation of Optimized Formulation for Physical and Chemical Parameters (Result are mean values ± SD)
Average Wt. (mg) n = 10	% Wt. Variation n= 10	Thickness (mm) n = 10	Diameter (mm) n = 10	Friability (%) n = 10
925.2 ± 0.42	+ 1.4 to - 3.1	8.42 ± 0.17	13.12 ± 0.15	0.38 ± 0.26
Hardness (kg/cm²) n = 6	% Drug content n = 10	Time for 20% drug release (hrs) n = 6	Time for 50% drug release (hrs) n = 6	Time for 90% drug release (hrs) n = 6
6.5 ± 0.29	100.8 ± 0.39	2	8	20

Table VIII: Kinetic modelling of drug release profile of optimized formulation

Model for Curve fitting	R² (regression coeff.)	k (Slope)	F (Fit test)	n value for Peppas model
First order	0.9844	0.1040	-	NA
Hixon Crowell	0.9924	0.0283	-	NA
Higuchi	0.9754	19.5867	-	NA
Baker–Lonsdale	0.9218	0.0098	-	NA
Korsmeyer - Peppas	0.9969	13.5069	1941.47	0.6377

Fig. 4 Dissolution profile of optimized formulation in different media.

show how the response changes when 2 factors are changed simultaneously.

The polynomial terms (X12 and X22) are included to investigate nonlinearity. The statistical analysis of the factorial design batches was performed by quadratic modelling using Design Expert software version 7.1.1. The T₂₀, T₅₀ and T₉₀ values for the 9 + 3 batches (Trials 1 to 12) showed a wide variation for which the results are shown in Table V. The data clearly indicate that the values of dependent variables are strongly dependent on the independent variables. The mathematical relationship constructed for the studied response variables are expressed as Eqns. 7, 8 and 9.

All the polynomial equations were found to be statistically significant (P < 0.05) as determined by ANOVA. The polynomial equation can be used to draw conclusions after considering the magnitude of coefficient with positive or negative signs.

T₂₀= + 2.04 + 0.50 * A + 1.00 * B + 0.25 * A * B - 0.13* A² + 0.38 * B² . . .Eqn. 7

(R squared - 0.8405 and adequate Precision - 8.370)

T₅₀ = + 7.83 + 0.67* A + 2.67 * B + 1.00 * A * B + 0.50 * A²- 1.50 * B² . . .Eqn. 8 (R squared - 0.9432 and adequate Precision - 14.230) and

T₉₀ = + 19.33 + 2.67* A + 5.33 * B + 0.000 * A * B - 2.00 * A² - 2.00 * B². . . Eqn. 9

(R squared - 0.9200 and adequate Precision - 12.0)

Overall responses in terms of time in hrs required to get the desired % drug release were found to be dependent on the amount of chitosan and HVO together as both the excipients are required to obtain the desired profile, it is clearly evident from the contour plots and response graphs in Fig. 3 that the amount of chitosan is mainly responsible to retard the drug release in later stage of the dissolution profile while the amount of HVO is responsible to control the initial drug release, although the composition containing lower concentration of chitosan as well as HVO did not work at all where T₉₀ was achieved in about 8 to 12 hrs. but as their concentration in composition increases the formulations tend to behave well in terms of drug release profile that is why the maximum concentrations of both the independent variable led to a formulation with strongly controlled dissolution parameters in terms of % drug release for example trial 8 and 9 with a T₉₀ value even above 20 and 24 hrs respectively hence optimum amounts of chitosan and HVO were required to get a desired T₂₀, T₅₀ and T₉₀ values, i.e. for trials 5, 6 and 7 these were 2, 8 and 20 hrs respectively with a slow initial and fast final release (trial 7) which is not desired hence trial 5 and 6 were highly desirable so the optimized trial with the concentrations range of dependent variables close to trial 5 or 6 was preferred and as per the solution obtained by the response methodology according to the values in Table IV, Optimization for the best composition was done by the Design Expert Software on the basis of the results obtained from the Factorial design trials and the various assumptions put in the form of constraints for the optimization solution exercise, the Constraints are discussed in Table V, only one possible solution to give best desired results is given in terms of a composition with 240 mg chitosan containing polymeric layer and 82 mg of HVO containing drug layer was defined in Table VI which upon evaluation found to be fitting perfectly for the responses in the desired range. The details of dissolution profile and evaluation of optimized formulation are described Fig. 4 and Table VII respectively.

Kinetic modelling of drug release:

Dissolution profile of the optimized formulation was fitted for the various model equations to check the behaviour of the release profile, out of the several equations tried Korsmeyer–Peppas was found to be the well fitted equation for the obtained dissolution profile ( Fig. 5) as compared to the other equations as having the highest and acceptable values of regression coefficient, slope and fit test as shown in Table VIII which indicates the dissolution behaviour of the formulation is polymeric and having more than one kind of release phenomenon which could be the diffusion and erosion kinds of as the drug layer is contained of HVO a lipid material which will allow diffusion of the drug but at the same time that lipid layer is covered from upper and lower sides hence the release form these two sides is controlled by the polymeric chitosan layer which govern the dissolution upon its erosion hence both type of mechanism involve in the studied formulation has been proved.

CONCLUSION:

Chitosan based extended release tablets of VNH were successfully formulated using HVO as an additional rate controlling excipient. The optimum concentrations of Chitosan and HVO in the composition were calculated on the basis of 3 level factorial design and response methodologies. Developed formulation found to be fitting peppas model allowing a diffusion and erosion controlled release phenomenon at the same time proved to be stable at accelerated conditions of temperature and humidity which was evidenced by drug excipient compatibility and formulation stability studies. Hence a 20 hrs dissolution profile of venlafaxine was achieved to delivery an once a day formulation of the same was developed and evaluated in terms of formulation and release parameters and proved that the chitosan can be successfully employed to develop a controlled release formulation of a freely water soluble drug.

Fig. 5 Dissolution profile of optimized formulation in different media.

REFERENCES:

1. Vishnu Patel, Madhabhai Patel, Rakesh Patel, Chitosan: A Unique Pharmaceutical Excipient, Drug Delivery Technology, 5, 2005, 6.

2. Mia Sakkinen, Biopharmaceutical evaluation of Microcrystalline cellulose as release rate controlling hydrophilic polymer in granules for gastro retentive drug delivery, Helsinki Thesis, October 2003, 1-9.

3. J. Nunthanida et. al., Characterization of chitosan acetate as a binder for sustained release tablets, Journal of Controlled Release, 2004, 99, 15-26

4. Sweetman S. Edited, Martindale the complete drug reference, Venlafaxine hydrochloride section, 34th Edition, 2007, Pharmaceutical Press, London, UK.

5. Troy SM, Parker VD, Fruncillo RJ, Chiang ST. The pharmacokinetics of venlafaxine when given in a twice-daily regimen, Journal of Clinical Pharmacology, 1995, 35, 404-409.

6. C. Lindsay DeVane, Immediate-Release Versus Controlled-Release Formulations: Pharmacokinetics of Newer Antidepressants in Relation to Nausea, Journal of Clinical Psychiatry, 2003, 64, 18, 14–19.

7. Steven M. Troy, Clifford Dilea, Patrick T. Martin, Amy S. Rosen, Richard J. Fruncillo, Soong T. Chiang, Bioavailability of once-daily venlafaxine extended release compared with the immediate-release formulation in healthy adult volunteers, Current Therapeutic Research, August 1997, 58, 8.

8. Sapna N. Makhija1, Pradeep R. Vavia, Once daily sustained release tablets of venlafaxine a novel antidepressant, European Journal of Pharmaceutics and Biopharmaceutics, 2002, 54, 9–15.

9. M. R. Bhalekar, A. R. Madgulkar, D. D. Sheladiya, S. J. Kshirsagar, N. D. Wable, S. S. Desale, Statistical Optimization of Sustained Release Venlafaxine HCl Wax Matrix Tablet, Indian Journal of Pharmaceutical Sciences, 2008, 70, 4, 472-476.

10. Mukesh Gohel and Shital Bariya; Fabrication of Triple-Layer Matrix Tablets of Venlafaxine Hydrochloride Using Xanthan Gum, AAPS PharmasciTech, 10, 2, 624-630.

11. Laurent Y. Galichet Ed., Clarke's Analysis of Drugs and Poisons, Pharmaceutical Press, London, UK, Third Edition, 2005

12. Deborah M. Sherman, John C. clark, John U. Lamer and Steven A. white, United States Patent 6403120, June 11, 2002.

13. Gothoskar A. V., Oza K. P., Rajabi A. R., Study of slow release matrix formulation of highly soluble drug (Venlafaxine HCl), Colorcon Asia Pvt. Ltd., Goa, India, Control Release Society, 2005.

14. Indian Pharmacopoeia, Government of India, Ministry of Health and Family Welfare, Delhi, Controller of Publication; 1996, 736.

15. Dissolution methods database, US FDA / CDER, Office of Generic Drugs, http://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutions.cfm?PrintAll=1.

16. Singh B, Ahuja N, Book review on Pharmaceutical Experimental Design, International Journal of Pharmaceutics, 2000, 195, 247-248.

17. State-Ease®, Design -Expert® Software, Version 7.1.1, USA.

18. Paulo Costa, Jose Manuel Sousa Lobo, Modeling and comparison of dissolution profiles, European Journal of Pharmaceutical Sciences, 2001, 13, 123–133.

19. SigmaPlot® exact graphs and data analysis, Version 10, Systat software Inc., USA.

20. Stability Testing of New Drug Substances and Products, Q1A(R2), International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use, http://www.ich.org/LOB/media/MEDIA419.pdf.

21. Yan Li, Xi Guang Chen, Nan Liu, Cheng Sheng Liu, Chen Guang Liu, Xiang Hong Meng, Le Jun Yu and John F. Kenendy, Physicochemical characterization and antibacterial property of chitosan acetates, Carbohydrate Polymers, 2007, 67, 2, 227-232.