INTRODUCTIONThemajority of the formulations available today are taken orally. It means thisroute of administration is most commonly used all over the world and most ofthe researchers are pulled in towards this class of formulation. The foremostobjective of the controlled drug delivery system is to minimize the dosingrecurrence. The elementary point of modified drug release formulations is toimprove a therapeutic regimen by providing prolonged and continuous action forpredetermined time period providing greater safety, efficacy and precision.
Bilayer tablet is the new age for the affluent development of modified drugrelease formulation. Bilayer tablet may be better than those routine utilizeddosage forms. Bilayer tablet is great suiting for sequential arrival of two medicamentsand it is also capable of partitioning the two contrario substances. It is alsosuited for sustain release tablets in which one layer is immediate release layerand another is sustain release layer.
Needof Bilayer TabletØ To modulatethe delivery rate of two or more different active pharmaceuticalingredients.Ø Toformulate the fixed dose combination of different APIs, increase the productlife cycle.Ø Tomodify the total surface area available for API layer either by sandwichingwith one or more inactive layers in order to attain swellable / erodiblebarriers for modified release.
Advantagesof Bilayer TabletØ Less expensive previously, value concerningillustration contrasted with different measurement structure. Ø Substantialphysical, chemical and microbiological steadiness as compared to other dosageform.Ø Unpleasantstench and bad taste can be conceal by using various coating technique.Ø Idealfor mass scale production.Ø Lighterand compact.Ø Versatileand Functional conceptØ Recognitionof product is straightforward and rapid necessitating no auxiliary steps whenemploying an embossed and/ or monogrammed punch face.
Disadvantageof Bilayer TabletØ Drugshaving bitter taste, drugs with unpleasant stench or drugs that are oxygensensitive might require coating.Ø Childrenand unconscious patient may find difficult to swallow it.Ø Drugshosting poor wettability, poor release profile are difficult to formulate.Ø Crosstainting might occur between two layers.
Ø CappingØ Severaldrugs refrain compression due to amorphous nature, low density character. Challenges in Bilayer ManufacturingIn spite of the aforementionedmerits of the bilayer tablets, there are several complication associated withthe mechanism and compression of bilayer tablets that have been reported in theliterature in recent years.Ø Crosscontamination: When the granules of one layer blend/mix with the granules ofother layer, cross contamination occurs. It may repress the purpose of thebilayer tablet.Ø Delamination:Tablet separates aside when they the two parts of the gadget do not bond witheach other.Ø Cost:Bilayer tablet is more expensive as compared to the traditional dosage forms.Ø Productionyield: Bilayer tablet have a lesser yield than single layer tablet.
VARIOUSTECHNIQUES FOR BILAYER TABLETa)EN SO TROL TECHNOLOGY: To increasesolubility to a magnitude or to formulate optimized medication dosage formShire laboratory utilized an coordinated methodology to drug delivery focusingon identification and incorporation of the identified enhancer into controlledrelease technology..b) Bilayer and trilayer OROS push pull technology:Thissystem is employed for the solubility issue Alza developed the L-OROS systemwhere a lipid soft gel product containing drug in a dissolved state isinitially manufactured and then coated with a barrier membrane, than osmoticpush layer and than a semipermeable membrane, drilled with an exit orifice. c)OROS® push pull technology: This techniquecomprises of two or more layers among which one or more layers are essentiallyof the drug and other layers consist of push layer. The drug layer mainly consistsof drug along with two or more different agents. So this drug layer comprisesof drug which is in poorly soluble form. There is further addition ofsuspending agent and osmotic agent. A semi permeable membrane surrounds thetablet core.
d) DUREDASTM TECHNOLOGY:(DUREDAS™Technology) is a technology which provides immediate or sustained release oftwo drugs or different release rates of the same drug in one dosage form. The tabletingprocess can provide an immediate release granulate and a modified-releasehydrophilic matrix complex as separate layers within the one tablet. Themodified-release properties of the dosage form are provided by a combination ofhydrophilic polymers.Benefitsoffered by the DUREDAS™ technology include1)Bilayer tableting technology.2)Tailored release rate of two medication components.3)Capability of two different Controlled Release Formulations combined.4)Ability for immediate release and modified release components in one tablet.5)Unit dose tablet.
e) PRODASor programmable oral drug absorption system PRODASis a mutliparticulate drug delivery technology that is primarily based on theencapsulation of controlled release minitablets in the size range of 1.5 to 4mm in diameter .This technology represents a combination of multiparticulateand hydrophilic matrix tablet technologies and thus provide the desired releaserates .These considerations may include immediate release delayed release and /or controlled release minitablets. In addition to controlled release absorptionover a specified period .PRODAS technology also enables targeted delivery ofdrug to specified sites of absorption throughoutthe GI tract .
Combination products also are possible by using minitabletsformulated with different ingredients. f)GEMINEX TECHNOLOGYInthis drug delivery system at different times more than one drug can bedelivered. This technology basically increases the therapeutic efficacy of thedrug by decreasing its side effects.
It is useful both to industry as well as patientas in single tablet it provides delivery of drug at different rates.g)ERODIBLE MOLDED MULTILAYER TABLET Egaleterodible molded tablets in an erosion based platform. It has the benefit ofdeliveringzero order or delayed release with minimum effect from the gastrointestinalenvironment.Egalet erodible molded multilayered tablets are prepared by injection mouldingegalet technology comprises of a coat and a matrix. Drug release is controlledthrough the gradual erosion of the matrix part. The mode and rate of releaseare designed and engineered by altering the matrix the coat and the geometry toachieve by altering the matrix the coat, the geometry to achieve either a zeroorder release or a delayed. For a zero order, a drug is dispersed through the matrix.
The coat is biodegradable but has poor water permeability to prevent its penetration.The matrix tends to erode when in contact with available water .The erosion ofthe matrix is caused by GI fluids and promote by gut movements in the GI tract.The drug release is mediated almost wholly by erosion because the dosage formis designed to slowdownthe water diffusion into the matrix .
It is definitely more desirable for drugswithchemicaland physical stability issues after contacting with water .Egalet deliverytechnologyis developed based on standard plastic injection molulding to ensure accuracy,reproducibility and low production cost.TYPES OF BILAYER TABLET PRESSA)Single sided tablet press.B)Double sided tablet pressC)Bilayer tablet press with displacement monitoring.D)Multilayer compression basicsA)Single sided pressVarioustypes of bilayer presses have been designed over the years .The simplest designis a single sided press with both chambers of the double feeder separated fromeach other. Each chamber in gravity fed , or force fed with a different powder, thus producing the two individual layers of the tablet .
When the die passesunder the feeder, it is at first loaded with the first layer of powder followedby the second-layer powder then the entire tablet is compressed in one or twosteps ( two pre and main compression) . The two layers in the die mix slightlyat their interface and in most cases bond sufficiently so that no layerseparation occurs when the tablet is produced this is the simplest way ofproducing a bilayer tablet.LIMITATIONS OFSINGLE SIDED PRESS? Noweight monitoring or control of the individual layers? Nodistinct visual separation between the two layers? Dwelltime due to the small compression roller possible resulting in poor deareationcapping and hardness problems.DWELL TIMEDwell time isdefined as the time during which compression force is above 90% of its peak value.Longer dwell time is the major factor in the production of quality tablets.COMPRESSIONFORCEMany bilayertablets require a first layer compression force of 100 daN in order to retainthe ability to bond with the second layer . above 100daN this ability may belost and bonding between both layers may not be sufficient.
this results in lowhardness bilayer tablets and might cause separation of the two layers.B)DOUBLE SIDED TABLET PRESSESMostof the double sided tablet presses which are automated production control usethe compression force to monitor and control the weight of the tablet weights. Theeffective compression force exerted on each individual tablet with the help ofthe compression system at the main compression of the layer. This system helpsin to reject out the tolerance tablets and correct the dies fill depth when required. ADVANTAGES1.Low compression force exerted on thefirst layer to avoid capping and separationof the individual layer.2.Increased dwell time at pre compression of both first and second layer toprovide sufficient hardness at maximum turret speed.
3.Maximum prevention of cross contamination between two layers.4.A clear visual separation between the two layers.5.Displacement weight monitoring for accurate and independent weight control ofthe individual layer.6.
Maximized yield.LIMITATIONSSeparationof the two individual layers is due to insufficient bonding between the twolayers during final compression of bi-layer tablet. Correct bonding is onlyobtained when the first layer is compressed at a low compression force so thatthis layer can still interact with the second layer during final compression.
Bonding is too restricted if first layer is compressed at a high compressionforce. The low compression force required when compressing the first layer unfortunatelyreduces the accuracy of the weight monitoring/control of the first layer in thecase of tablet presses with “compression force measurement”. Most of the doublesided tablet presses with automated production control use compression force.
3)BILAYER TABLET PRESSES WITH DISPLACEMENTTheprinciple of bilayer tablet press is fundamentally different from the principleof compression force. In this case the accuracy increases with reducedcompression force .At higher production speed the risk of capping and separationincreases but can be reduced by sufficient dwell time at all four compression stages.
ADVANTAGES· Displacement weight monitoring/controlfor accurate independent weight control of the individual layers.· Increased dwell time atprecompression of both first and second layer to provide sufficient hardness atmaximum turret speed· Maximum prevention ofcross contamination between the layers.· A clear visualseparation of the layers· Maximized yield .
4)MULTILAYER COMPRESSION BASICS Pressescan be designed specifically for multilayer compression or a standard doublepress can be converted for multilayer. The multilayer tablets concept has beenlong utilized to develop sustained release formulations such tablets have fastreleasing layer and may contain bilayer or triple layers to sustain drugrelease from the tablet. The pharmacokinetic advantage relies on the fact that drugrelease from fast releasing granules leads to sudden rise in bloodconcentration however the blood level is maintained at a steady state as thedrug is released from the sustained granules.
PREPARATIONOF BILAYER TABLETBilayertablets are prepared with one layer of drug for immediate release with thesecond layer designed to release drug later, either as a second dose or in anextended release form. The bilayer tablets with two incompatible drugs can alsobe prepared by compressing separate layers of each drug so as to minimize areaof contact between two layers. An additional intermediate layer of inertmaterial may also be included.COMPACTIONToproduce adequate tablet formulation, certain requirements such as sufficient mechanicalstrength and desired drug release profile must be met. At times, this may be difficulttask for formulator to achieve these conditions especially in bilayer tablet formulationwhere double compression technique is involved, because of poor flow andcompatibility characteristic of the drug which will result in capping and/orlamination. The compaction of a material involves both the compressibility andconsolidation.COMPRESSIONItis defined as reduction in bulk volume by eliminating voids and bringingparticles intoClosercontacts.
CONSOLIDATIONItis the property of the material in which there is increased mechanical strengthdue to interparticulate interaction (bonding). The compression force on layer 1was found to be major factor influencing tablet delamination. 5)DIFFERENT TYPES OF BILAYER TABLET PRESSESA)PICCOLA BILAYERThisrotary press was designed to represent two-layer tablet productionconditions at a small scale, according to the needs of new productdevelopment.
Piccola Bi-layer press meets cGMP standards and can use type D or Btooling complying with TSM or EU standards, which allows the employment of the samepunches used in production. For an appropriate adjustment in tablet production,there are totally independent systems for weight, height and hardnessadjustment, both for the first and second layers. A PLC system having a touchscreen and software designed for Galenic Development and Production Controlallows the integrated control of all parameters, including production rate and,separately, the rate of each of the star forced feeder. There are varied accessoriesand options for the software used; such as the possibility of weight controlduring production and the use of data obtained for calculation and statistics.B)ROTAB BILAYERa)SoftwareItis modular designed software to which additional functions can be added.PCsystem with 15″touchscreens is an advanced system which provides fast graphicalevaluations with accurate results.b)WorkingRoTabbilayer when using is switched to production mode.
Dose and compressionforceis automatically regulated by adjusting filling speed and die table. Hardnessis also regulated when required.c)R and D modified techniqueRand D modified RoTab Bilayer is featured with measuring points on which thereare graphical visualization and evaluation are possible. There is an additionalalarm function on which punch tightness is controlled. Anytime upgration ispossible which is R and D Plus.d)R and D Plus.
Rand D Plus provides improved standards in tabletting technology with allimportantfunctionssuch as punch tightness control display of force displacement and tabletscraper force.C) BILAYER TABLET PRESS The Xm bilayer tablet press features a rectangle second layerfeeder that permits automated first layer sampling at production speeds . Thefirst layer sampling capability also offers a hardening feature , which the maincompression station will automatically compress , the first layer tablet forin-process measurement .The two feeders are zero clearance and are configuredwith an integrated dust extraction manifold which cleans the dis table andcompletely eliminates any potential of cross contamination .wipcon® solution available for potent for layer tablet press is asmall scale press which is ideal for product development, scale up, clinicaltrials and midrange production . The bilayer execution, single layer conversionkit and exchangeable turret offers, a new standard in GMP with extremeaccessibility to the compression zone and a combination of quick disconnectsand smooth surfaces that permit fast cleaning and changeover the machineconcept:-ADVANTAGESFlexible concept.
Bilayer execution with optional single layer.QUALITY ANDGMP-REQUIREMENTSToproduce a quality bi-layer tablet, in a validated and GMP-way, it is importantthat the Selected press is capable of five:1.Preventing capping and separation of the two individual layers that constitutethe bi-layer tablet2.Providing sufficient tablet hardness3.Preventing cross-contamination between the two layers4.
Producing a clear visual separation between the two layers5.High yield Accurate and individual weight control of the two layers.Theserequirements seem obvious but are not so easily accomplished.EVALUATIONOF BILAYER TABLETA) PARTICLE SIZE DISTRIBUTIONThe particle size distribution was measured using sieving method.
B) PHOTON MICROSCOPE STUDYPhoto-microscope image of TGG and GG was taken (X450magnifications) by photomicroscope.C) ANGLE OF REPOSEThe diameter of the powder cone was measured and the angle ofrepose was calculated using the following equation.Tan Ø=h/rWhere h and r are the height and radius of the powder cone.D) MOISTURE SORPTION CAPACITYAll disintegrates have capacity to absorb moisture from atmospherewhich affectsmoisture sensitive drugs. Moisture sorption capacity was performedby taking 1 g of disintegrate uniformly distributed in Petri-dish and kept instability chamber at 37±1°C and 100% relative humidity for 2 days and investigatedfor the amount of moisture uptake by difference between weights.E) DENSITYThe loose bulk density (LBD) and tapped bulk density (TBD) weredetermined and calculatedusing the following formulas.LBD ¼ weight of the powder=volume of the packing ð2ÞTBD ¼ weight of the powder=tapped volume of the packing ð3ÞF) COMPRESSIBILTYThe compressibility index of the disintegrate was determined byCarr’s compressibility index.C = 100 x (1-ÞB/ÞT)(Indian Pharmacopoeia, 1996; United States Pharmacopoeia,2000:1944).
G) HAUSNERS RATIOIt is calculated by the formula, freely settled bulk density ofthe powder tapped density of the powder 7) EVALUATION OF SUSTAIN RELEASE BILAYER TABLET A) TABLET THICKNESS AND SIZEThickness and diameter of tablets were important for uniformity oftablet size.Thickness and diameter was measured using venire caliper.B) TABLET HARDNESSThe resistance of tablets to shipping or breakage under conditionsof storage,transportation and handling before usage depends on its hardness.
The hardness of tablet of each formulation was measured by Monsanto hardnesstester. The hardness was measured in kg/cm2.C) FRIABILITYFriability is the measure of tablet strength.
Electrolab EF- 2friabilator (USP) was used for testing the friability using the following procedure.Twenty tablets were weighed accurately and placed in the tumbling apparatusthat revolves at 25 rpm dropping the tablets through a distance of six incheswitheach revolution. After 4 min, the tablets were weighed and thepercentage loss in tabletweight was determined.% loss = (Initial wt. of tablets – Final wt. of tablets)/ Initialwt. of tablets ×100.
D) UNIFORMITY OF WEIGHTTwenty tablets were selected at random and the average weight wascalculated. WeightVariationwas calculated and was compared with I. P. standards.
E)DISSOLUTION STUDIESBilayertablets were subjected to in vitro drug release studies in simulated gastricandIntestinalfluids to assess their ability in providing the desired controlled drugdelivery . Drug release studies were carried out using USP dissolution testapparatus I at 100 rpm,37±0.5°C,and pH 1.2 buffer (900 ml) (i.e.
0.1N HCl) for 2 hours, since the averagegastric emptying time is about 2 hours. The dissolution medium was replacedwith pH 6.8 phosphate buffer (900ml) and experiment continued for another 10hours. At different time intervals, 5ml of the samples were withdrawn andreplaced with 5ml of drug-free dissolution medium. The samples withdrawn wereanalyzed by UV spectrophotometer using multi component mode of analysis.CONCLUSIONBilayertablet is improved beneficial technology to overcome the shortcoming of thesingle layered tablet. There is various application of the bi-layer tablet itconsist of monolithic partially coated or multilayered matrices.
Bilayer tabletis suitable for sequential release of two drugs incombination,separate two incompatible substances and also for sustained release tablet inwhichone layer is immediate release as initial dose and second layer is maintenancedose. Thepreparationof tablets in the form of multi layers is used to provide systems for theadministration of drugs, which are incompatible and to provide controlledrelease tablet preparations by providing surrounding or multiple swellinglayers. Bilayer tablet quality and GMP-requirements can vary widely. Thisexplains why many different types of presses are being used to produce bi-layertablets, ranging from simple single sided presses to highly sophisticatedmachines such as the Courtoy-R292F. Whenever high quality bilayer tablets needto be produced at high speed, the use of an ‘air compensator’ in combinationwith displacement control appears to be the bestSolution.