2013 http://informahealthcare.com/pdt ISSN: 1083-7450 (print), 1097-9867 (electronic) Pharm Dev Technol, 2014; 19(1): 103–115 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10837450.2012.757785 Preparation of sustained-release dosage form of Venlafaxine HCl using liquisolid technique M. Khanfar, M. Sheikh Salem, and Faiza Kaddour Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan Abstract Context: The aim of this study is to control the dissolution rate of Venlafaxine HCl. Objective: To prepare sustained release tablets of Venlafaxine HCl. Material and methods: Different liquisolid formulations, liquid vehicles, drug concentration in the liquid medication and different ratios of carrier to coating material (R) were prepared. The prepared powders were characterized for possible interactions between drug and excipients using differential scanning calorimetry, X-ray, Fourier transform infrared analysis and scanning electron microscopy. Powder flowability was also evaluated, then they are compressed at different compression forces, and the compressed tablets were evaluated for their mechanical properties and dissolution profile. Results: Release results show that sustained release behavior can be obtained from liquisolid formulation containing Tween 80 as liquid vehicle. Discussion: Many factors affect the retardation effect of Venlafaxine HCl such as the type of liquid vehicle, drug concentration in the liquid medication and R. The mechanism of the in vitro release profiles was found to be mainly controlled by diffusion and polymer relaxation. Conclusion: Sustained release formulation of Venlafaxine HCl was attained using the liquisolid technique. Keywords Eudragit RS PO, liquisolid, sustained release, Venlafaxine HCl History Received 1 September 2012 Revised 29 November 2012 Accepted 30 November 2012 Published online 24 January 2013 Introduction Sustained-release dosage forms are pharmaceutical dosage forms that provide a slower drug release compared to immediate-release dosage forms when given by the same route 1,2 . Sustained release formulations are designed to release the drug slowly at a rate enough to give the appropriate therapeutic response and to prolong the therapeutic activity for a certain period of time 2,3 . This type of dosage form offers many advantages over conven- tional immediate-release dosage form. They reduce the frequency of dosing; they provide an increase in safety margin of highly potent drugs and they are more economical than conventional immediate-release dosage forms. Several attempts have been made to prepare sustained release formulations for drug molecules such as preparation of polymeric systems 4,5 , microencapsulation 6–8 , preparation of insoluble salt form of drug molecules 9 and preparation of sustained release tablet of drug molecules using the matrix system 10,11 . Recently, the liquisolid technique is used to prepare sustained release matrix tablets. It is a quite new and promising technology that can alter and modify drug dissolution rate and thereby producing desirable sustained release system 12–14 . This technique is based on the conversion of liquid drug or drug solution or suspension into dry powder with good flowability and compressibility characteristics. This conversion is attained by simple mixing of such liquid medication with calculated amount of certain excipient known as the carrier and coating material 15,16 . A mathematical model has been introduced in order to calculate the precise amounts of the excipients (carrier and coating materials) needed to produce a free flowing powder. In that model the maximum liquid load on the bulk powder material, termed as the ‘‘loading factor’’ is determined, and hence the amounts of both the carrier and coating materials can be calculated. Many factors could be optimized to obtain acceptable retardation effect from liquisolid formulations such as type of carrier material used, the ratio (R) of the carrier to coating material, type of liquid vehicle used and the amount and type of matrix- forming agent added. Production of liquisolid compacts is simple and similar to that of directly compressed tablets. It has a lower cost of production compared to other techniques because it does not require sophisticated machinery and advanced preparation procedures 17 . Venlafaxine HCl is an antidepressant drug selective serotonin and norepinephrine inhibitor 18 , it has high water solubility (572mg/ml). It is a novel antidepressant, which is very effective in treating depression and antisocial disorders. It has a short half life necessitating administration 2 or 3 times daily to maintain the therapeutic plasma level and thus the drug efficacy. Preparation of sustained-release dosage form can enhance patient compliance, convenience, improve tolerability, effectiveness and the safety of the drug. In this study, sustained-release dosage form of Venlafaxine HCl will be prepared using the liquisolid technique which is a new and promising method with low cost and industrial applicability. Address for correspondence: M. Khanfar, Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 30303, Irbid 22110, Jordan. Tel: 00962-2-7201000, ext 23537. Fax: 962-2-7201075. Mobile: 962-777510765. E-mail: [email protected]; [email protected]Pharmaceutical Development and Technology Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/18/14 For personal use only.
Pharm Dev Technol, 2014; 19(1): 103–115! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10837450.2012.757785
Preparation of sustained-release dosage form of Venlafaxine HCl usingliquisolid technique
M. Khanfar, M. Sheikh Salem, and Faiza Kaddour
Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
Abstract
Context: The aim of this study is to control the dissolution rate of Venlafaxine HCl.Objective: To prepare sustained release tablets of Venlafaxine HCl.Material and methods: Different liquisolid formulations, liquid vehicles, drug concentration inthe liquid medication and different ratios of carrier to coating material (R) were prepared. Theprepared powders were characterized for possible interactions between drug and excipientsusing differential scanning calorimetry, X-ray, Fourier transform infrared analysis and scanningelectron microscopy. Powder flowability was also evaluated, then they are compressed atdifferent compression forces, and the compressed tablets were evaluated for their mechanicalproperties and dissolution profile.Results: Release results show that sustained release behavior can be obtained from liquisolidformulation containing Tween 80 as liquid vehicle.Discussion: Many factors affect the retardation effect of Venlafaxine HCl such as the type ofliquid vehicle, drug concentration in the liquid medication and R. The mechanism of the in vitrorelease profiles was found to be mainly controlled by diffusion and polymer relaxation.Conclusion: Sustained release formulation of Venlafaxine HCl was attained using the liquisolidtechnique.
Received 1 September 2012Revised 29 November 2012Accepted 30 November 2012Published online 24 January 2013
Introduction
Sustained-release dosage forms are pharmaceutical dosage formsthat provide a slower drug release compared to immediate-releasedosage forms when given by the same route1,2. Sustained releaseformulations are designed to release the drug slowly at a rateenough to give the appropriate therapeutic response and toprolong the therapeutic activity for a certain period of time2,3.This type of dosage form offers many advantages over conven-tional immediate-release dosage form. They reduce the frequencyof dosing; they provide an increase in safety margin of highlypotent drugs and they are more economical than conventionalimmediate-release dosage forms.
Several attempts have been made to prepare sustained releaseformulations for drug molecules such as preparation of polymericsystems4,5, microencapsulation6–8, preparation of insoluble saltform of drug molecules9 and preparation of sustained releasetablet of drug molecules using the matrix system10,11. Recently,the liquisolid technique is used to prepare sustained release matrixtablets. It is a quite new and promising technology that can alterand modify drug dissolution rate and thereby producing desirablesustained release system12–14. This technique is based on theconversion of liquid drug or drug solution or suspension into dry
powder with good flowability and compressibility characteristics.This conversion is attained by simple mixing of such liquidmedication with calculated amount of certain excipient known asthe carrier and coating material15,16. A mathematical model hasbeen introduced in order to calculate the precise amounts of theexcipients (carrier and coating materials) needed to produce a freeflowing powder. In that model the maximum liquid load on thebulk powder material, termed as the ‘‘loading factor’’ isdetermined, and hence the amounts of both the carrier andcoating materials can be calculated.
Many factors could be optimized to obtain acceptableretardation effect from liquisolid formulations such as type ofcarrier material used, the ratio (R) of the carrier to coating material,type of liquid vehicle used and the amount and type of matrix-forming agent added. Production of liquisolid compacts is simpleand similar to that of directly compressed tablets. It has a lower costof production compared to other techniques because it does notrequire sophisticated machinery and advanced preparationprocedures17.
Venlafaxine HCl is an antidepressant drug selective serotoninand norepinephrine inhibitor18, it has high water solubility(572 mg/ml). It is a novel antidepressant, which is very effectivein treating depression and antisocial disorders. It has a short halflife necessitating administration 2 or 3 times daily to maintain thetherapeutic plasma level and thus the drug efficacy. Preparation ofsustained-release dosage form can enhance patient compliance,convenience, improve tolerability, effectiveness and the safetyof the drug. In this study, sustained-release dosage form ofVenlafaxine HCl will be prepared using the liquisolid techniquewhich is a new and promising method with low cost and industrialapplicability.
Address for correspondence: M. Khanfar, Department of PharmaceuticalTechnology, Faculty of Pharmacy, Jordan University of Science andTechnology, P.O. Box 30303, Irbid 22110, Jordan. Tel: 00962-2-7201000,ext 23537. Fax: 962-2-7201075. Mobile: 962-777510765. E-mail:[email protected]; [email protected]
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Materials
Venlafaxine HCl was supplied by United Pharmaceuticals,Amman, Jordan. Avicel PH 101 (microcrystalline cellulose,MCC) and Aerosil 200 (Colloidal silicon dioxide) were obtainedfrom the Jordanian Pharmaceutical Manufacturing Company,Amman, Jordan. Eudragit RS PO was obtained from EvonikRom Gmbh Pharma Polymers, Germany. HPMC K100 MCRpremium was supplied by Colorcon, Dartford, UK. Magnesiumstearate (MgSt) was obtained from Fizmerk India Chemicals,Hapur, India. Crabopol 971 PNF was supplied by the ArabPharmaceutical Manufacturing Company, Amman, Jordan.Polyethylene glycol 400 (PEG 400) was supplied by ApplichemGmbH, Germany. Tween 80� (polyoxy ethylene (20) sorbitanmonooleate) was supplied by Techno Pharmchem, Bahadurgarh,India. Propylene glycol (PG) was supplied by Panreac, Monteplet& Esteban SA, Barcelona, Spain. Methanol (high-performanceliquid chromatography (HPLC) grade) was supplied by FisherChemical, Epsom, Surrey, UK. Sodium hydroxide was supplied byFrutarom Ltd, Billingham, Teesside, UK. Potassium dihydrogenorthophosphate and dipotassium hydrogen orthophosphate areobtained from Guangdong Guangua Chemical Factory, Shantou,Guangdong, China.
Methods
Analysis of Venlafaxine HCl
HPLC analysis was used to determine the concentration ofVenlafaxine HCl. The column used was ACE 5 C18, 125 mm� 4.0 mm (ACE, Portage la Prairie, Manitoba, Canada). Themobile phase for isocratic elution consisted of phosphate buffer0.05 M, methanol (40:60, v/v). The column oven temperature wasset at 25 �C� 1 �C. The detection wavelength was 224 nm and theinjection volume was 20 ml. Calibration curve was constructed byinjection of eight standard solutions with concentrations of 1.562,3.125, 6.250, 12.500, 25, 50, 100 and 200mg/ml.
Solubility studies
Saturated solutions of Venlafaxine HCl in the liquid vehicles(Tween 80�, PEG 400�, and PG) were prepared, shaked in thewater bath at 25 �C. After 48 h, the equilibrium was attained andsamples were centrifuged until precipitation of excess powder andthe supernatant was filtered through a 0.45-mm pore size filter. Thefiltrates were suitably diluted and analyzed using HPLC, and drugconcentrations were obtained. All experiments were done intriplicate.
Determination of the loading factor, flow properties andapplication of the mathematical model
In order to obtain the equation that describes the relation betweenthe loading factor and the ratio of the carrier and coating material,and from which the liquid retention potential of the carrier andcoating materials for every nonvolatile liquid can be determined, amathematical model was used based on the flow properties of themixture of powder, where several liquid powder admixtures wereprepared for the three liquid vehicles used at four different ratios(R) of carrier and coating materials5,10,15,19. For each R value,10 g of powder (total weight of carrier and coating material) wasmixed with increasing amount of liquid.
Evaluation of the flowing properties of the powder was carriedout using angle of slide measurement in which 10 g of theprepared powder was placed on a metal surface with constantthickness. The surface was tilted gradually until the powder startsto slide and the angle of slide was recorded. Angle of slide versusliquid fraction curves was constructed and the angle of 33� wasconsidered as the optimum.
The loading factor at each R value was calculated andthe equation was constructed by plotting the loading factor againstits corresponding 1/R value from which the liquid retentionpotential of both carrier (intercept) and coating (slope) isdetermined.
Preparation of conventional and liquisolid powders
Formulations containing microcrystalline cellulose as a carriermaterial
Several liquisolid formulations denoted as LS1 to LS7 wereprepared using three nonvolatile liquid vehicles Tween 80�
(polyoxy ethelene (20) sorbitan monooleate), PEG 400 and PG,Avicel 101 as carrier material and Aerosil 200 as coating material.Different concentrations of drug medication and different Rvalues were used. The composition of the prepared liquisolidformulations is shown in Table 1.
The loading factor at different R value was calculated from thelinear equations after determination of the liquid retentionpotentials. In the preparation of liquisolid formulations,Venlafaxine HCl was added to liquid vehicle in 100-mL glassbeaker and mixed for 5 min. Then the specified amount of carrierwas added to the liquid medication in the glass beaker andtransferred into a mortar and mixed for 5 min. A specified amountof coating material was added to the mixture with continuousmixing for another 5 min. Finally, 20% (wt/wt) of HPMC as amatrix forming agent was added to the final mixture withcontinuous mixing.
For comparison purpose, a batch of 100 conventional tablets(DCT1) was prepared. Each tablet contains 37.5 mg ofVenlafaxine HCl, 300 mg of Avicel 101, 60 mg of Aerosil 200(weight ratio of Avicel and Aerosil is 5) and 99.37 mg of HPMCas a matrix forming agent (20% of tablet weight). VenlafaxineHCl was mixed with Avicel and Aerosil for 5 min using a mortarand pestle, after that HPMC was added with continuous mixingfor another 5 min.
Formulation containing Eudragit RS powder as a carrier material
Different liquisolid formulation containing Eudragit RS PO as acarrier material, termed as LS8 to LS14, were prepared. Threeliquid vehicles were used: Tween 80� (polyoxy ethelene (20)sorbitan monooleate), PEG 400 and PG. Eudragit RS PO was usedas a carrier and Aerosil 200 was used as a coating material.Different drug concentration in liquid medication was used (30%,40% and 50%) with different R values (2, 5 and 8). Allformulations contain 1% of MgSt as lubricant and 3% of carbopol971 PNF as a binder and they are illustrated in Table 1. A batch of100 liquisolid tablets was prepared for every formula in the samemanner as described with liquisolid formulation containing Avicelas a carrier material.
Additionally, a batch of 100 tablets for the conventionalformula (DCT2) was prepared. Each tablet contains 37.5 mg ofVenlafaxine HCl, 400 mg of Eudragit RS PO, 50 mg of Aerosil200 (weight ratio of Avicel and Aerosil is 8), 4.924 mg of MgSt asa lubricant (1% of tablet weight) and 15.077 mg of carbopol 971PNF as a binder (3% of tablet weight). Venlafaxine HCl wasmixed with Avicel and Aerosil for 5 min using a mortar andpestle, after that MgSt and carbopol were added with continuousmixing for another 5 min.
Finally, all liquisolid formulation and conventional formula-tions were compressed at different compression pressure to give atensile strength between 13 and 14 kgf/cm2 for formulationscontaining Avicel 101 as a carrier material and between 6 and8 kgf/cm2 for formulations containing Eudragit RS PO as a carriermaterial. All prepared tablets were compressed using an IR
104 M. Khanfar et al. Pharm Dev Technol, 2014; 19(1): 103–115
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hydraulic press with a punch of 12 mm in diameter and from thetensile strength versus compression force curve the suitablecompression force for each formula was determined.
Characterization of the prepared powder
Differential scanning calorimetric analysis
Differential scanning calorimetric (DSC) thermogramsfor Venlafaxine HCl, Avicel, Aerosol 200, HPMCK-100 CR,Eudragit RS PO, MgSt, carbopol, conventional formulationsand all prepared liquisolid formulations were recorded. Samplesof 5� 0.3 mg were heated under nitrogen in sealed aluminiumpans from 10 �C to 300 �C, at a scan rate of 10 �C/minusing Metler DSC. An empty aluminium pan was used as areference.
X-ray powder diffraction analysis
Powder X-ray diffraction patterns for Venlafaxine HCl,Avicel101, Aerosil 200, Eudragit RS powder, Venlafaxine–Avicel physical mixture (1:1), Venlafaxine–Aerosil physicalmixture (1:1), Venlafaxine–Eudragit RS physical mixture (1:1),liquisolid formulations and for conventional formulation wererecorded with X-ray powder diffractometer using cobalt radiation,at a voltage of 40 kV and a current of 30 mA.
Fourier transform infrared analysis
Fourier transform infrared analysis (FT-IR) spectra forVenlafaxine HCl, Avicel 101, Aerosil 200, HPMC, EudragitRS PO, liquisolid formulations and conventional formulationswere measured using potassium bromide (KBr) powder. Sampleswere blended with KBr powder and grounded in a mortar with anagate pestle until the sample was well dispersed, then a smallamount of the powder was analyzed. FT-IR analysis wasconducted over a frequency range of 4750–500 and 0.04 cm�1
resolution.
Scanning electron microscopy
Scanning electron microscopy (SEM) was used to examinethe shape and surface of Venlafaxine, silica particles, micro-crystalline cellulose, Eudragit RS PO and liquisolid systems. Priorto the examination, samples were mounted on an aluminum stubusing double adhesive carbon films. They were sputter-coatedwith platinum under vacuum to render them electricallyconductive.
Flow properties
Angle of slide was measured as described earlier.
Carr’s compressibility index and Hausner’s ratio
Powder flow properties were tested by measuring bothCarr’s compressibility index (CI) and Hausner’s ratio (HR). CIand HR were calculated according to Equations (1) and (2) asfollows:
Carr’s index ¼ �tap � �bulk
�bulk
� �� 100 ð1Þ
Hausner’s ratio ¼ �tap
�bulk
ð2Þ
where �tap and �bulk are the tapped and bulk densities,respectively.
The tapped and bulk densities were measured after determina-tion of the tapped and bulk volumes. Fifteen grams of theprepared powder was placed in a 100-ml cylinder; the volume ofthe poured powder is the bulk volume. The cylinder was tapped1000 times using jolting tap densitometer. The tapped volume wasthe resulting volume after tapping.
Evaluation of the compressed tablets
Crushing strength (hardness) of tablets
The force (N) required for crushing the tablet diametrically wasmeasured using Copley Hardness Tester (Copley Scientific Ltd,Nottingham, UK). Since different formulations have differenttablet weights, the specific hardness was measured according toEquation (3) to compare the mechanical properties of the tablets.
Specific crushing strength ¼ Crushing strenght kgfð ÞTablet wtðgmÞ ð3Þ
Tensile strength determination
After the determination of the suitable compression force for eachprepared formulation, the tensile strength was calculated toevaluate mechanical properties of compressed tablets. Equation(4) was used to calculate the tablet tensile strength
T ¼ 2H
�DtTt
ð4Þ
Table 1. The composition of liquisolid formulations containing Avicel and Eudragit RS as carrier materials.
aAvicel pH 101 was used as a carrier (formula LS1–LS7), while Eudragit was used as a carrier in formula (LS8–LS14).bHPMC was used as a matrix forming agent in formula (LS1–LS7), while Carbapol PNF (3%) was used as a binder in formula (LS8–LS14).
DOI: 10.3109/10837450.2012.757785 Preparation of sustained-release dosage form of Venlafaxine HCl 105
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where T is the tablet tensile strength, H is the tablet hardnesswhich was measured using Copley Hardness Tester (CopleyScientific Ltd), Dt and Tt are the tablet diameter and tabletthickness, respectively. They were measured using a digitalmicrometer.
Friability testing
Tablets friability was measured using an Erweka friabilator(Erweka, Heusenstamm, Germany). For each formula, 20 tabletswere weighed accurately (Wi) and then rotated in the friabilatorfor 4 min with a rotational speed of about 25 rpm. Then the tabletswere dedusted and the weight after (Wa) performing the test wasmeasured. The percent friability was measured as shown inEquation (5):
% Friability ¼ Wi �Wa
Wi
ð5Þ
Release studies
All release studies were performed in triplicates using USPdissolution apparatus II (paddle method) (Erweka, Heusenstamm,Germany), under sink condition, at 37 �C � 0.1 �C and 50 rpm.The dissolution test for the prepared tablets was carried out in900 ml phosphate buffer solution of pH¼ 6.8. A sample of 5 mlwas carefully withdrawn at predetermined time intervals andreplaced with fresh dissolution media. The samples were filteredusing 0.45-mm Cameo nylon syringe filter (Sigma-AldrichFoundation,Taufkirchen, Germany and then assayed forVenlafaxine HCl content by injecting 20 ml into the HPLC.Percent cumulative of drug released was plotted against time andthe release characteristics were studied.
The best formula which gave the desirable release behaviorwas selected for further dissolution in pH 1.2 under the followingconditions: 900 ml of 0.1 N hydrochloric acid solution, pH 1.2, at37 �C� 0.1 �C and 50 rpm. The release study was conducted for2 h to simulate drug release in the gastric medium. Allexperiments were done in triplicate.
The dissolution profiles were compared by calculating thesimilarity factor (f2) according to Equation (6):
f2 ¼ 50� log 1þ 1=nð ÞXn
t¼1
Rt � Ttð Þ2" #�0:5
�100
8<:
9=; ð6Þ
where n is the number of time points, t is the sampling time, Rt isthe dissolution value of the reference formula at time t, Tt is thedissolution value of the compared formula at time t. The twodissolution profiles are declared similar if f2 is greater than 50.
Aging studies
The effect of temperature and humidity on the dissolution andcrushing strength of liquisolid formulation were determinedby storing nine tablets of formulation LS1, LS7 and LS8 at
30 �C/65% RH, and 40 �C/75% RH. The samples weremaintained in the preset humidity chambers for a storage periodof 3 months.
After this period of time, samples were tested for theircrushing strength (n¼ 6) and their dissolution profile (n¼ 3) atthe conditions that have been used with freshly prepared tablets.The results were compared with the freshly tested tablets.
Results and discussion
Solubility studies
In order to choose the best nonvolatile solvent to suspend the drugmolecules, solubility of Venlafaxine HCl was carried out. Thesolubility of Venlafaxine HCl in Tween 80�, PEG 400� and PG isillustrated in Table 2.
According to the results obtained, Venlafaxine HCl does nothave the same solubility in the three liquid vehicles used. Thetable shows that Venlafaxine HCl has the lowest solubility inTween 80�. In spite of the high HLB value of Tween 80 due to itshigh hydrophilicity, compared with other liquid vehicles used, ithad the lowest solubilization effect on Venlafaxine HCl. This maybe due to other physicochemical properties of this nonvolatilesolvent that decrease drug solubilization capacity such asviscosity (425 mPa s), molecular weight (1310 g/mol) and chemi-cal structure (extremely branching structure). Solubility of drugmolecules plays an important role in dissolution rate; the highersolubility may lead to higher dissolution rate. Since the goal of thecurrent study was to slow down the dissolution rate ofVenlafaxine HCl, Tween 80� was used as the liquid vehicle inthe preparation of liquisolid systems. The effect of nonvolatilesolvents type on the release behavior of Venlafaxine fromliquisolid tablet systems was investigated and the results arediscussed as follows.
Flowable liquid retention potential and liquid loadingfactor determination
The mathematical model for Avicel 101 with Aerosil 200� indifferent liquid vehicles was obtained from previous work done inour labs20. The mathematical equations are shown in Table 2.
In the current study, the mathematical model for Eudragit RSpowder with Aerosil 200� in Tween 80�, PEG 400� and PG wasdetermined, and the results are shown in Figure 1.
Figure 1 shows the weight of liquid per unit weight of powderversus its corresponding angle of slide for the three liquid vehiclesat four different ratios (R). After plotting the angle of slide againstthe liquid fraction in the liquid powder admixture, the liquidfraction that is corresponding to 33� was taken as the maximumamount of liquid that the system can hold with maintaining goodflowability.
Maximum fraction ¼ Maximum amount of oil
Qþ qð Þ ð7Þ
Table 2. Solubility of Venlafaxine HCl in nonvolatile liquid vehicles and the loading factor of Avicel and Eudragit in different liquid vehicles.
106 M. Khanfar et al. Pharm Dev Technol, 2014; 19(1): 103–115
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Lf ¼W
Qð8Þ
Using the above two equations (7 and 8), we can calculatethe loading factor for every R value. Then every loading factorwas plotted against the reciprocal of the ratio (1/R), which willresult in a linear equation possessing a slope that is equal to theliquid retention potential of the coating and an intercept that isequal to the liquid retention potential of the carrier material.Liquid retention potential for Eudragit RS PO and Aerosil 200� issummarized in Table 2.
Eudragit RS PO and Aerosil 200 have shown different flowableliquid retention potential with different liquid vehicles used. Theliquid retention potential or the maximum amount of nonvolatilesolvent that an excipient can retain inside it bulks whilemaintaining acceptable properties depends on the excipientnature and also on the liquid vehicle absorbed or adsorbed.Silica (Aerosil 200�) has shown higher liquid retention potentialsin all liquid vehicles compared with Eudragit RS PO. This can beexplained by the higher specific surface area of silica particles(200 m2/g)21 compared with that of Eudragit RS PO. The highadsorption capacity of silica particle is due to the increased specificsurface area of silica particles and is confirmed by higher loading
Figure 1. Application of the mathematical model for (1) angle of slide measurements at different R values and (2) liquid retention potentialdetermination of carrier (Eudragit RS PO�) and coating material (Aerosil 200�). (A) Tween 80, (B) PEG 400 and (C) PG.
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factors obtained when the carrier/coating ratio (R) has beendecreased (high percentage of silica particles) in all liquid vehicles.
The liquid retention potential of the carrier will depend on theproperties of the liquid vehicle added and its ability to diffuse intothe bulk of the carrier particle by absorption mechanism which isa diffusion and a filling process22.
Fluid penetration into a porous material is a process ofcapillary-driven flow which depends on both fluid properties andinteraction between the fluid and the porous material. It has beenshown that the penetration rate of a liquid into a porous structureis dependent on the balance between capillary and opposingviscous forces which are given in equation:
L2 ¼ 2m� cos �t
k�ð9Þ
where L is the penetrating length at time t, m is the pore size, g isthe surface tension of the liquid, � is the contact angle between theliquid and solid, � is the viscosity of the liquid, k is a constant thatdepends on the pore shape23.
From Equation (9), it is clear that the penetration or theabsorption of liquids by a porous material depends on manyfactors: pore size of the absorbing structure, surface tension of theliquids with powder particles which also affect the contact angleand the viscosity of the fluids. Smaller pore size can restrict theentrance of the liquid vehicle with large molecular weight andextremely branching structure. Otherwise small pores create largecapillary pressure which results in high flow driving force forliquid of low molecular weight. A high surface tension betweenthe porous particles and the liquid vehicle leads to high contactangle which decreases the maximum diffused amount of theliquid vehicles.
PEG 400 and PG have shown high liquid retention potentialwith Eudragit RS PO, and this may be attributed to theirhydrophilicity and low molecular weight that facilitate theirpenetration inside the powder particles. While Tween 80� hasshown the lowest liquid retention potential with Eudragit RS PO;this may be due to its large molecular weight and branchingstructure that limits its entrance and diffusion through the pores ofthe carrier particle into its bulk.
Comparing the mathematical model obtained in the currentstudy using Eudragit RS PO as a carrier and Aerosil 200 as acoating material and that from previous research20, it was shown
that Eudragit RS PO has higher liquid retention potential than thatof Avicel PH 101�. This can be explained by the large particlesize of Eudragit RS PO (133.6 mm) and low surface area comparedwith that of Avicel PH 101� (73.33 mm). Liquid retentionpotential of silica with Avicel as a carrier was higher than thatwith Eudragit RS PO using the same liquid vehicle. The liquidretention potential of the coating particles depends on the type ofthe coating material and the adsorbed liquid, and also on thearrangement of the particles and liquid distribution on the surfaceof the carrier material. Carrier particles with large specific surfacerequire higher amount of silica to adsorb excess of liquid on theirsurface since the distribution of the liquid vehicle will be on alarger scale compared with that of carrier with low specificsurface area.
Characterization of the powder
Powder flow characterization
Flow properties of the prepared formulations were evaluatedusing angle of slide, Carr’s index and Hausner’s ratio. An angle ofslide of 33� is considered as the limit of acceptable flowability22.
Carr’s index (compressibility index) and Hausner’s ratio areimportant factors in characterizing the interparticles friction.According to the USP, powders are considered to have passableflow properties if Carr’s index is less than 25%. Carr’s index andHausner’s ratio for the prepared formulations are represented inTable 3.
Both conventional and liquisolid formulations showed accep-table flow properties. Angle of slide for all prepared formulationwas less than 33 �C. Flow character or type or flow was betweengood for formulation LS6, LS7, LS13, LS14, with a Carr’s indexless than 16% and Hausner’s ratio less than 1.19. All theremaining formulations have a fair flowability except LS2 whichshows a very poor flowability.
DSC analysis
Venlafaxine HCl has shown a sharp melting endotherm at212.6 �C, this sharp endothermic peak indicates thatVenlafaxine HCl was used in its crystalline state. Avicel 101has shown a broad endothermic peak at 137.5 which correspondsto the dehydration and evaporation process. DSC thermogram ofEudragit RS PO has shown an amorphous structure with an
Table 3. Carr’s index (CI %), Hausner’s ratio (HR), angle of slide, hardness, specific crushing strength, tensile strength and friability of liquisolid andconventional formulations.
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endothermic peak at approximately 180 �C which may correspondto the degradation and decomposition of the polymer. Aerosil 200has not shown any peak. DSC thermogram of conventionalformulations has shown the same endothermic peak correspond-ing to the drug melting with less intensity than pure drug alonedue to the presence of other excipients in a larger percentage thanthat of the drug. The liquisolid formulations have also shown thesame endothermic peak of the drug with lower intensity comparedto that of the crystalline drug due to the partial solubilization ofdrug in liquid vehicle. Endothermic peak corresponding todehydration and evaporation of water from the excipients wasobserved in both conventional and liquisolid formulations.
X-ray powder diffraction analysis
The X-ray powder diffraction (XRD) presented in Figure 2showed that pure Venlafaxine is present in a crystalline state andit has expressed sharp peaks at 2� values of 6.5, 8.3, 12.5, 13.6,15.5, 18.9, 21.9, 25.3, 28.5, 31.5 and 35.2. Aerosil 200 is presentin an amorphous form, MCC has shown broad characteristicpeaks and Eudragit RS PO was in amorphous state. Thecharacteristic peaks of the drug in conventional formulationshave been masked by that of the carrier materials which constitutea huge portion of the formula. X-ray diffraction patterns ofliquisolid formulations have shown disappearance of the char-acteristic peaks of Venlafaxine HCl due to partial solubilization ofdrug in the liquid vehicle used.
Fourier transform infrared analysis
Fourier transform infrared (FT-IR) analysis was carried out toprovide structural information about the molecules and to detectany possible interaction between drugs and excipients in the sameformulation.
Interaction between compounds will be detected by a changein the specific position or complete disappearance of thecharacteristic stretching vibration of the molecule.
FT-IR spectra of Venlafaxine HCl, pure excipients andphysical mixtures are shown in Figure 3.
The FT-IR spectrum for Venlafaxine HCl shows one absorp-tion band at 3348.5 cm�1. This band represents the intermolecularhydrogen bond. The aromatic C–H stretching frequency of thepure drug appears around 3014.74, 3076.46 and 3101 cm�1. Thealiphatic C–H stretching appears at 2935.6, 2922 and
2856.5 cm�1. N–CH3. HCl stretching frequency appears at 2860and 2629 cm�1. C¼C aromatic appears at 1612.4–1581.6 cm�1.The O–CH3 stretching frequency appears at 1274.9–1246 cm�1.
The FT-IR spectra obtained from physical mixture showedpeaks which were a summation of the characteristic peaksobtained with the pure drug and pure polymers indicating thatthere was no chemical interaction in the solid state between thedrug and different polymers used. FT-IR spectra of conventionaland liquisolid formulations are shown in Figure 6. Thecharacteristic peaks of Venlafaxine were observed in the twoconventional formulae DCT1 and DCT2 but a decrease in itsintensity has occurred which may be due to higher percentage ofcarrier material (MCC and Eudragit, respectively) with respect todrug. All liquisolid formulations have shown nearly a similarspectrum to that of conventional formula, which is an indicationof the absence of the drug–liquid interaction.
Formulations containing Tween 80 as liquid vehicle and Avicelas carrier have shown additional peak at approximately1730 cm�1 which corresponds to (C¼O) stretching in Tween80. FT-IR spectra of DCT2 and LS8 show an intense peak at this
Figure 2. X-ray powder diffraction of (A) Venlafaxine, Aerosil, MCC, physical mixture (Venlafaxine: MCC), conventional formula (DCT1) andliquisolid formula (LS1) and (B) X-ray powder diffraction of Venlafaxine, Aerosil, Eudragit RS PO, physical mixture (Venlafaxine: Eudragit RS PO),conventional formula (DCT2) and liquisolid formula (LS8).
Figure 3. FT-IR spectra of Venlafaxine HCl, conventional and liquisolidformulations.
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frequency which correspond to (C¼O) stretching in Eudragit,carbopol and Tween 80.
Scanning electron microscopy
Figure 4 shows the scanning electron microscopy (SEM) resultsof the drug (Venlafaxine HCl) carrier (Avicel PH 101� andEudragit RS PO), coating material (Aerosil 200) and liquisolidsystems. Venlafaxine HCl appears to be crystalline in nature withregular shape. Avicel PH 101 appears fibrous in shape, whileAerosil appears to have an amorphous shape with a very smallparticle size. Eudragit RS appears to have regular shape withsmooth surface. SEM results of liquisolid formulations at twomagnification powers have shown the absence of the crystallinedrug particles and the presence of the adsorbed silica particles onthe surface of microcrystalline cellulose and Eudragit.
Evaluation of the tablets
Hardness, tensile strength and friability measurement
Mechanical properties of tablets are among the importantparameters that commonly used to evaluate the tablet quality. Inthe current study, hardness, specific crushing strength, tensilestrength and friability were determined to evaluate mechanicalstrength of the prepared tablets, and the results are shown inTable 3. Specific crushing strength was calculated to compare thehardness of tablets with different weight.
All prepared formulations were compressed to give the sametensile strength. All liquisolid formulations have shown lowerspecific hardness compared with that of conventional formula-tions. This may be due to the presence of liquid vehicle that may
hinder the formation of interparticle bonding, mainly hydrogenbonds.
Formulations containing Avicel as carrier material have showna higher specific crushing strength compared with that containingEudragit RS PO. This difference may attributed to two factors:first, Avicel have lower particle size and hence high surface area,resulting in more contact points between particles and so increasethe bonding and crushing strength and second, Avicel is known tohave high compressibility and compactability due to its plasticdeformation during compression which also leads to more bondsholding the Avicel particles.
From Table 3, it is shown that the percentage of Avicel inliquisolid formulations containing this excipient as a carrieraffects the specific crushing strength proportionally.
All prepared formulations have shown accepted percent offriability. The friability results were consistent with the crushingstrength results. Formulations with higher specific crushingstrength have been less friable than those with lower specificcrushing strength.
Release studies
The effect of type of liquid vehicle, drug concentration in liquidmedication, the weight ratio between the carrier and the coatingmaterial and pH of dissolution medium on drug release arestudied and the results are shown and discussed as follows.
Effect of type of liquid vehicle and carrier material on drugrelease
Figure 5(B) shows the effect of type of the liquid vehicle on drugrelease in liquisolid formulation containing Avicel as a carrier
Figure 4. Scanning electron micrograph of (A) Venlafaxine HCl, (B) Avicel PH 101, (C) Aerosil 200, (D) Eudragit RS PO and (E) liquisolid system.
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material. It was shown that the type of liquid vehicle affectssignificantly the drug release from liquisolid system. Liquisolidformulations containing Tween 80 as a liquid vehicle showedslower drug release and in turn better sustained release effect ofdrug compared to that containing PEG (f2¼ 46.089) and PG(f2¼ 26.170). While Figure 5(A) shows drug release fromformulations containing Eudragit RS PO as a carrier, LS8which contains Tween 80 as a liquid vehicle shows betterretardation release in comparison with LS9 (PEG as liquidvehicle) and LS10 (PG) and dissolution profiles differ signifi-cantly (f2 of LS8 and LS9 ¼ 36.269, f2 of LS8 and LS10 ¼46.159). For both carriers, Tween 80 shows the best retardationeffect which may be due to the lower solubility of VenlafaxineHCl in this liquid vehicle compared to that in PEG and PG.
Comparing the release from liquisolid formulation (LS1 andLS8) and these in directly compressed tablets, the retardation ismore in liquisolid formulations.
The difference between liquisolid formulations and conven-tional formulations is the presence of liquid vehicle which is themain cause of slow release from liquisolid tablet. An importantcharacteristic of Tween 80 or polysorbate 80 is its plasticizereffect, by these properties it reduces glass transition temperatureof polymer used in the formulation. During tablet compressionprocess, the glass transition temperature of the carrier may beexceeded which gives a better coalescence of the polymer
particles. The resulted matrix will have a fine network withlower porosity and higher tortuosity, and during the release thepolymer network surrounds drug molecules and restricts drugleaching, which sustains the drug release.
From Figure 5, it is also shown that liquisolid formulationsprepared using Avicel as a carrier and HPMC as a matrix formingagent give better sustained release effect of drug over approxi-mately 12 h in comparison with that prepared using Eudragit RSPO as a hydrophobic carrier, which sustains drug release over amaximum period 9 h. This significant difference (f2¼ 28.722)may be contributed to the potential effect of HPMC in reducingdrug release from liquisolid hydrophilic matrix due to swellingand gel layer formation on the surface of tablet.
Effect of drug concentration in the liquid vehicle on drug release
Drug concentration in liquid medication is an important parameterin drug release from liquisolid tablet. It was found in previousresearch that increasing drug concentration in liquid medicationdecreases the drug release significantly20,24,25. The slow releasecan be explained by the fact that at high concentration of drug inliquid medication, only a small fraction of the drug will be in themolecular state which decreases drug release according to theNoyes–Whitney equation25,26. In the current study, the effect ofdrug concentration on drug release behavior was studied and the
Figure 5. (A) Dissolution profile of LS1 (Tween 80), LS2 (PEG 400), LS3 (Propylene glycol) and DCT1. (B) Dissolution profile of LS8 (Tween 80),LS9 (PEG 400), LS10 (Propylene glycol) and DCT2.
Figure 6. Effect of drug concentration in liquid medication on drug release from liquisolid formulations containing (A) Eudragit RS PO as a carrierand (B) Avicel as a carrier.
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results were shown in Figure 6. From Figure 6(B), it appears thatLS1 formulation that has 30% drug in liquid medication withAvicel as carrier gives slower drug release compared with theircounterpart liquisolid formulation containing 40% and 50% drug inliquid medications but similarity factor result shows that thedissolution profile of LS1 (30% drug) and LS4 (40%) was similar(f2 ¼ 54.592) and significant difference was observed betweendissolution profile of LS1 (30%) and LS5 (50%) with a similarityfactor equal to 46.318. Formulation of LS8 that has 30% drug inliquid medication with Eudragit RS PO as a carrier and Tween 80as a liquid vehicle gives slower drug release compared with theircounterpart liquisolid formulation containing 40% and 50% drug inliquid medications, and dissolution profiles were significantlydifferent with similarity factor of 47.502 and 33.304, respectively.This increase in drug release by increasing drug concentration inliquid medication may be explained by increasing the fraction ofundissolved drug in liquid medication due to partial solubilizationof Venlafaxine HCl in Tween 80, which will dissolve rapidly andalso by decreasing drug concentration in liquid medication a higheramount of carrier material is required to convert liquid medicationinto dry powder with good flowability and compactibility proper-ties that may slow the drug release. This result indicates that theretarding effect of elevated amount of carrier material is higherthan the retarding effect of drug concentration in liquisolidformulations.
Effect of carrier and coating ratio on drug release
The effect of carrier and coating excipient ratio R on drug releasebehavior of liquisolid tablet was studied and the results are shownin Figure 7(A and B) for formulations containing Avicel andEudragit RS PO as carrier material, respectively.
It was shown that drug release from liquisolid formulationdecreases by increasing carrier to coating ratio. The slowestrelease in liquisolid formulation containing Avicel as a carriermaterial was obtained from LS7, which has a ratio of 8 followedby LS4 with a ratio of 5 and the highest release obtained fromLS6 with a ratio of 2. Significant difference was observed onlybetween dissolution profile of LS6 with R value of 2 and LS7 withR value of 8 (f2 of LS6 and LS7¼ 41.871). Liquisolidformulations with high R value contains larger amount of carriermaterial (Avicel) and smaller amount of fine coating material andrelatively elevated amount of swelling or matrix forming agent(HPMC) compared to their counterpart with low R value.
Therefore, the decreased release rate of drug particle fromliquisolid compacts of high R value may be due to the slowdiffusion of liquid medication through the high amount of highlyporous carrier material during the drug release and also due to theswelling rate of HPMC and effective gel layer formed on thesurface of liquisolid tablets.
In liquisolid formulation containing Eudragit RS PO, theslowest release also observed in liquisolid formula with thehighest R value which was LS8 with a ratio of 8 followed by LS14with a ratio of 5 and highest release obtained from LS13 with aratio of 2. According to similarity factor result, significantdifference in dissolution profile was observed only between LS8(R¼ 8) and LS13 (R¼ 2) with f2¼ 33.134. The higher amount ofEudragit RS PO as hydrophobic carrier in LS8 at higher ratio maybe the reason for the slow drug release from such formulation.
Effect of pH of dissolution medium on drug release from liquisolidformulations
Liquisolid formulations LS7 and LS8 which gave the bestretardation effect were selected to study the effect of changingthe pH of the dissolution medium on Venlafaxine HCl releasefrom liquisolid formulations. The release study was carried out intwo media, phosphate buffer solution of pH 6.8 and 0.1 N HClsolution adjusted to pH 1.2. The results are shown in Figure 8(A),Venlafaxine HCl is a basic drug with pKa value of 9.2. Therefore,an acidic pH would increase the release rate of the drug byincreasing the solubility and dissolution rate. Figure 8(B) showsonly a slight increase in the amount of drug released; this increasewas more pronounced in LS8 due to the ionization of quaternaryammonium in Eudragit RS PO which increases the permeabilityof the polymer. According to the similarity factor, this increasewas not significant which indicates the good formulation proper-ties that release the drug at a sustained manner even in a highlyacidic medium.
Release kinetics of Venlafaxine HCl from preparedliquisolid tablets
To determine the mechanism of drug release from liquisolidtablets, various kinetic models were used. The obtained drugrelease data were analyzed using the following mathematicalmodels: zero-order kinetic, first-order kinetic, Higuchi kinetic andHixson-Crowell kinetic. Linearity (coefficient of correlation) wasused to select the most appropriate kinetic model.
Figure 7. Effect of carrier and coating ratio on drug release from liquisolid formulation containing (A) Eudragit RS PO as a carrier and (B) Avicel asa carrier.
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The correlation coefficients for all the release kinetics werecalculated by using linear regression analysis. The results arepresented in Table 4. The table shows that the in vitro release ofVenlafaxine HCl from liquisolid formulations gave the bestlinearity (R2 was between 0.987 and 0.998) in Higuchi model plotin comparison with zero-order and first-order model. Thisindicates that the release rate of drug molecule depends onsquare root of time and it is controlled by Fickian diffusion. TheHixson–Crowell model indicates the nonchange of surface areaand diameter of the tablet during dissolution process of matrix asfunction of time (0.525�R2� 0.681) which confirms that thediffusion is the main mechanism of drug release.
The release exponent (n) indicates the mechanism of drugrelease was 0.455n50.89 for all liquisolid formulations, whichindicates according to Table 4 anomalous transport (non-Fickiandiffusion) for all formulations where the drug release is acombination of diffusion and polymer relaxation. R2 is thecoefficient of correlation: K0 (h�1), K1 (h�1), Kh (h�1/2) and KHC
(h�1/3) are the release rate constants for zero-order, first-order, theHiguchi model and the Hixson–Crowell model, respectively, andn is the release exponent of the Korsmeyer–Peppas model.
Aging studies
Effect of temperature and relative humidity on hardness ofliquisolid formulations
The hardness of fresh and aged tablets is shown in Table 5. Thecrushing strength of liquisolid formulations was affected by the
storage at high humid conditions. Liquisolid formulationscontaining Avicel as a carrier material (LS1 and LS7) haveshown a decrease in their hardness; this decrease was morepronounced at 40 �C/75% RH, but they still have acceptablehardness and can withstand handling. This decrease may be due tomoisture sorption into cellulose structure which increasemolecular mobility of MCC and reduce intermolecular attractionforces27. Liquisolid formulation containing Eudragit RS PO as acarrier (LS8) has shown an increase in its hardness. The increasewas more pronounced at 40 �C/75% RH. The glass transitiontemperature of Eudragit RS PO is 50 �C28. The presence of Tween80 may reduce this temperature by its plasticizing effect; hence athigh temperature of storage, the glassy state of polymer may beaffected, which alters the physical properties of tablets12.
Figure 8. Effect of pH of dissolution medium on drug release from liquisolid formulations containing (A) Eudragit RS PO as carrier and (B) Avicel asa carrier.
Table 4. Mathematical modeling and drug release kinetics of liquisolid formulations.
Kinetic models
Zero-order First-order Higuchi model Hixson–Crowell Korsmeyer–Peppas model
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Effect of temperature and relative humidity on rate of liquisolidformulations
Effect of aging on the dissolution rate of Venlafaxine HCl fromliquisolid formulations is shown in Figure 9. The main mechanismof drug release from liquisolid formulations was found to becontrolled by the diffusion of the drug and relaxation of thepolymer chain. The elevated temperature and humidity duringstorage of these formulations can affect relaxation of polymerchain which may affect the drug release rate. The storage ofliquisolid formulation LS1 at 30 �C/65% RH had no significanteffect on the release rate of the drug with similar dissolutionprofile (f2¼ 54.112), while the storage of this formulation at40 �C/75% RH increased the dissolution rate of drug andsignificance difference was observed between their dissolutionprofile (f2¼ 44.334).
The storage of liquisolid formulation LS7 at 30 �C/65% RHand 40 �C/75% RH had no significant effect on the release rate ofthe drug with similar dissolution profile (f2¼ 88.091 andf2¼ 71.240, respectively).
The storage of liquisolid formulation LS8 at 30 �C/65% RHhad no significant effect on the release rate of the drug withsimilar dissolution profile (f2¼ 51.7028), while this formulationgave a higher dissolution rate when stored at 40 �C/75% RHcompared with freshly prepared tablet with significant difference(f2¼ 39.790). This may be explained that at high temperature ofstorage (40 �C), the glass transition temperature of the polymermay be exceeded in the presence of plasticizer and caused themovement and redistribution of polymer chain in the tablet matrixwhich could be the cause of the change in mechanical propertiesof tablet and in turn the dissolution rate of drug molecules28.
Conclusion
Traditional technology to attain sustained release of the tablet ofVenlafaxine HCl failed to give the one because of the extremesolubility of this drug or the obtained tablets were eitherphysically unstable or dissolved very rapidly in dissolutionmedia29,30. In the current work, sustained release tablets ofVenlafaxine HCl were prepared satisfactorily using liquisolidtechnique. The obtained powders showed a good flowability andcompressibility behavior with no capping problems duringcompression process. Liquisolid formulations have shown abetter sustained release effect in comparison with directlycompressed tablets. The type of liquid vehicle was found toaffect the drug release significantly. Tween 80 gave the slowestrelease from liquisolid tablets. Low drug concentration and higherratio of carrier to coating material gave a better retardation effect.Liquisolid formulations containing Avicel as a carrier, HPMC as aretarding agent and Tween 80 as a liquid vehicle are able to
prolong drug release over a period of 12 h, on the other hand,liquisolid formulations containing Eudragit RS PO as a carrierand Tween 80 as a liquid vehicle sustained the release of drugover a maximum period of 9 h. Release kinetic study showed thatthe main mechanism of drug release was a combination ofdiffusion and polymer relaxation with release exponent between0.45 and 0.89. The release rate from liquisolid tablet has notaffected by its storage at 30 �C/65% RH for 3 months. Suggestedfuture work includes in vivo investigation of the drug bioavail-ability from prepared tablets.
Declaration of interest
The authors acknowledge the financial support provided by JordanUniversity of Science and Technology. The authors report no declarationof interest.
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