Hot melt extrusion:An industrially feasible approach for casting orodispersible fi lm

Hot melt extrusion:An industrially feasible approach for casting orodispersible fi lm

ARTICLEINFO

Article history∶

Received 28 December 2014

Received in revised form

17 February 2015

Accepted 1 March 2015

Available online 12 March 2015

∶

Extruders

Film forming polymers Plasticizers

Die swell phenomenon Quality by design

Scale up

Over the recent few decades,many groups of formulation scientists are concentrating on rapidreleasedosageformsinoralcavity.Amongallfastreleasedosageforms,orodispersible fi lms are successful to attract pharmaceutical industry due to ease of formulation and extension patent life.Films are popular in patients too because of quick onset and user friendliness of dosage form.From the beginning,solvent casting has been selected as method ofchoiceformanufacturing of orodispersible fi lms.Solvent casting hasbeen proved as a benchmark technology because of ease in product development,process optimization, process validation and technology transfer to production scale despite of some drawbacks like more number of unit operations involved and consumption of large quantity of solvents with controlled limits of organic volatile impurities in fi nal formulation.The application of hot-melt extrusion(HME)in the pharmaceutical industry is consecutively increasing due to its proven innumerable advantages like solvent free continuous process with fewer unit operationsandbettercontentuniformity.Veryfewdevelopmentactivitieshasbeeninitiated in the fi eld of hot melt extruded orodispersible fi lms so far.This extensive review covers detaileddiscussionofheavydutyindustrialextruders,selectionofdownstreamequipments, selection of excipients,common problems found in formulations and their remedies.Successive part of review addresses identi fi cation of critical quality attributes,quality target pro fi le of product,criticality in selection of process parameters and material for substantial simulation in laboratory scale and production for successful technology transfer.

?2015 Shenyang Pharmaceutical University.Production and hosting by Elsevier B.V.This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/ licenses/by-nc-nd/4.0/).

1. Introduction

The oral route is most preferred route of administration for drug delivery due to the aspect of patient compliance[1]. Nowadays,research and development activities on new active pharmaceuticalingredients (API)are remarkably less compared to new dosage form development of already existing molecules.New dosage form development of previouslyapproved API with satisfactory regulatory acceptance is itself a challenge for formulation scientist[2].Among the pharmaceutical dosage forms,the conventional tablet seems to be most popular.However,for the elderly and the infants,conventional tablet presents some dif fi culties for swallowing while liquid dosage forms are preferred[3].Looking to the development history of oral solid,it can be said that drawback of one dosage form has been worked as a seed for implanting new dosage form.Chewable tablets have been accepted to those who cannot swallow tablets easily but the disadvantage of chewable tablet was the chalky taste,gritty particles and unpleasant taste of active[4-6].Dispersible tablets and effervescent tablets,which were predissolved in a glass of water before consumption,solved some of these issues but use of insoluble lubricants resulted in a“scum”or dirty insoluble residue fl oating on the surface of the solution or on the sides of the container created patient discomfort[7].

To combine the advantages of tablets and liquids,the research activities has been focused on developing orodispersible tablets(ODTs)which are solid dosage forms that disintegrate rapidly in oral cavity within 1 min with improved ease of administration for patients who are mentally ill,disabled,uncooperative,pediatric and geriatric population[8,9].Freezedrying,sublimation,cotton candy,melt granulation,molding, phase-transition,spray-drying and effervescent technology are someofthewidelyacceptedtechniquesforpreparationofODTs [10,11].ODTs have been proved as a successful dosage form more than three decades.Cardinal Health's R.P.Scherer Corporation has patented Zydis technology which has been in commercialproductionsince1986[12-14].Otherfast-dissolvingoral technologies have been introduced last few decades,such as Lyoc,Orasolv,WOWTAB and Flashtab[15,16].Despite of commercial success,there are some drawbacks of ODTs like hygroscopicity,friability and unpleasant taste of active.Hence, theyneedprotectionfrommoistureand ODTsarevery brittlein nature which calls for specialized product packaging[17].Since these tablets dissolve directly in the mouth,taste masking of bitteractiveisalsoanimportantfactor[18,19].Thedrawbacksof ODThaveevolvedtheeraoforalwafersororalstriptechnology. Oral strip technology is mainly categorized in two parts, mucoadhesive fi lms and fl ash release wafers[20].

1.1. Mucoadhesive fi lms

Mucoadhesive fi lm is applied to buccal and gingival mucosa and sticks to mucosal surface.Carbomers 974P and 971P are mostwidely used polymersforbioadhesion purpose. Mucoadhesive fi lms are generally prepared by the methods such as hot melt extrusion and solvent casting[21,22].As per the function and disintegration time,mucoadhesive fi lms are categorized in two parts.(A)Mucoadhesive melt away strip:It sticks to the mucosa;totally dissolve within few minutes and continuously release the drug over time.Melt away fi lms are prepared as monolayer fi lms.(B)Mucoadhesive sustained release fi lm:This type of wafer sticks to mucosa and remain there for up to several hours.For that duration,drug release is sustained and wafer must be removed at the termination of medication[23,24].Oramoist is a sustained release oral wafer that adheres to the roof of mouth and enhances salivary secretion to prevent dry mouth syndrome(xerostomia)[25]. Sustained release fi lms are prepared as monolayer as well as multilayer multiparticulate containing fi lms[26-28].

1.2. Flash release wafers

Flash release wafers dissolve in maximum of 60 s and immediately release the drug in oral cavity.As per the site of application,the fl ashreleasewafers are categorizedin two parts.(A) Orodispersible fi lm(ODF):The ODF is ultrathin strip,which is similar to postage stamp in shape and size,with actives and mostlywatersolubleexcipientslike fi lmformingpolymersand plasticizers.Theorodispersible fi lms(ODFs)havelargersurface areacomparedtoODTsthatleadstorapiddisintegrationinoral cavity.Unlike the ODTs which are fragile and brittle,ODFs are fl exible enough with adequate ease of transport and handling. Unlike the other liquid dosage forms,precise dosing and unit dose formulation is possible with ODFs.ODFs provide ease of swallowing and patient can take it without need of water.So, patientswithdysphagia,repeatedemesis,motionsicknessand mental disorders can take it easily.ODF is commercially successful dosage form[29].Under the brand name of Triaminic thin strips,Novartis has developed many combination therapiesforlongactingcough,coughwithrunnynoseandcoldwith stuffy nose[30].Listrine pocket pouches,launched by P fi zer, have proved ODF as commercially successful dosage form[31]. Kwang Dong formulated Sedera-ondansetron 50 mg loaded ODF in South Korea with appreciable taste masking of highly bitter active with maximum drug loading which is itself a big challenge to formulation scientists[32].(B)Sublingual fi lms: Formulation of these types of fi lms is same as ODFs but the fi lms are placed under a tongue rather than in oral cavity. Reckitt Benckiser pharma formulated Suboxonebuprenorphine and naloxone sublingual fi lms which are used for maintenance treatment of opoid dependence[33].

Solvent casting is widely accepted for formulating fl ash release formulations[34].In this technique,water soluble polymers,activeandplasticizeraredissolvedinwaterorother solvent; fi nallycastedanddriedintraydryer[35-37].Stillthere are some problems associated with solvent casting like number of unit operations involved and consumption of organic solventswith controlled limits of organic volatile impurities in fi nal formulation.Field of hot melt extruded ODFs has been remained untouched till now.Hot melt extrusion is a continuous process without solvent and provides better content uniformity with fewer unit operations[29].Successive part of this review article explores the hot melt technology as scientist-friendly and commercially viable technique with considerable emphasis on scale up model as well as formulation development as per quality by design approach.

2. Hot melt extrusion equipments used in orodispersible fi lm formulation

Pharmaceutical-class extruders have evolved and adapted to mix drugs with carriers for various solid dosage forms.As per the requirement of dosage form,minor changes in con fi guration are adopted.In this section,different part of extruders has been discussed with specialemphasis on ODF formulation.

2.1. Types of extruders

2.1.1. Ram extruder

Ram extruder operates with a positive displacement ram capableof generating high pressures to push moltenmaterials through the die.Ram extruders are generally not preferred in ODF preparation by HME due to its low temperature uniformity and improper mixing abilities[38].

2.1.2. Screw extruder

Screw extruders are most widely accepted for pharmaceutical industry.Screw extruder consists of a rotating screw inside a heated barrel.Unlike ram extruder,a screw extruder provides more shear stress and intense mixing[38].In pharmaceutical industry,two types of screw extruders are widely used as per requirement of product.(A)Single screw extruder:One screw rotates inside the barrel and is used for feeding,melting, devolatilizing and pumping.Intense mixing is not achieved with single screw extruder[38].(B)Twin screw extruder:Twin screw extruders utilize two screws inside the heated barrel. Twin screw extruders have several advantages over single screw extruders,suchas easier material feeding,high kneading and dispersing capacities;less tendency to overheat and shorter transit time[39].Twin screw extruders are further classi fi ed as per their installation and working mechanism of screw.One is co-rotating and another is counterrotating design.In co-rotating extruder designs,screw rotates in same direction and they can be operated at high screw speeds and achieve high outputs,while maintaining good mixing and conveying characteristics.In counter-rotating extruders,screw rotates in opposite direction.The counterrotating designs are utilized when very high shear regions are needed as they subject materials to very high shear forces. Generally,it suffers from disadvantages of potential air entrapment,high-pressure generation and low maximum screw speeds and output[40].Basic structural difference of different variants of screw extruders is shown in Fig.1.

2.2. Parts of extruders

At a minimum,a screw extruder consists of three distinct parts like(a)conveying system for material transport and mixing(rotating screw,feed hopper and a temperature controlled barrel),(b)gear pump to eliminate inevitable small fl uctuation in process,(c)die system for forming different shapes,(d)downstream auxiliary equipment for cooling,cutting or collecting the fi nished goods.Additionally,commercial grade systems include mass fl ow feeders to accurately meter materials into the feed hopper,process analytical technology to measure extrudate properties(near infra red systems and laser systems),liquid and solid side stuffers,and vacuum pumps to devolatize extrudates or fi lm ribbons,roll collectors and calendaring equipment [41-44].

2.2.1. Screw element

The screws are the heart of any screw extruder and the design directly impacts the quality of the dosage form.Screw elements are fl ighted(threaded)for material transport,and non fl ighted to create shear regions for melting or mixing. Screw designs can be shear-intensive and/or shear-passive according to required mechanism of mixing[38,42].

2.2.2. Barrel

Barrels for screwextruders can be either one-piece or modular and can be con fi gured for downstream feeding like side stuf fi ng and venting.Barrel sections are heated by electric heaters.Barrel heating and cooling facilitates a temperature set point to maintain the desired melt viscosity within the process section.Temperatures throughout the process are normally controlled by electrical heating bands and monitored by thermocouples[38,45].

The screw along with the entire length of barrel is typically divided into three sections.(A)Feeding section:The purpose of the feeding section is to transfer the materials from the hopper to the barrel.(B)Compression or melting section:Channel depth decreases in this section,so it creates pressure which removes entrapped air.The polymer typically begins to soften and melt in the compression zone.(C)Metering zone:When material comes to metering zone,the polymer blend already exists inthe moltenstate.The function ofthe meteringzoneis to reduce the pulsating fl ow thus prevent the uneven material delivery to die and ultimately prevents the weight variation in fi nal ODF formulations[38].

2.2.3. Side stuf fi ng port provision

In pharmaceutical industry,incorporation of heat sensitive activesand fl avorsaremostdif fi cultinODFpreparedbyHME.This problemcanbeeliminatedwithprovisionofsidestuf fi ngportin barrel.The side stuf fi ng port is just far enough from the die to allow homogeneous mixing of active with already molten polymer-plasticizermatrixbutcloseenoughtothedietoreduce the exposure time to elevated temperature.Bruce et al.[46]reported incorporation of heat sensitive taste masked coated dextromethorphan hydrobromide granulesin previously moltenpolymerplasticizerblendbysidestuf fi ngportwhichwas justneartothedie.So,APIwasnotexposedtohightemperature required for melting of polymers.In area nearby side stuf fi ng port,mixing of API with already molten polymer-plasticizer blend is done at lower temperature compared to melting zone temperature.APIand fl avorsareexposedtoheatforfewminutes because residence time inside the extruder is less.

2.2.4. Gear pump

If fl ow of molten mass from barrel to die is uneven and fl uctuating,then it creates weight variation as well as uneven fi lm formation which ultimately create content variability.To eliminate inevitable small fl uctuations in extruder output and to assure consistent material fl ow into die,gear pump is installed in line between the end point of barrel and the die. The gear pump is positive displacement pump that precisely meters the melts to the die and that can build and maintain a constant output pressure.It can buffer inevitable small variationsinmaterialin fl owandinputpressureoftheextruder[46].

2.2.5. Die system

Die is attached at the end of extruder.The shape of the die determines the physical form or fi nal shape of the fi lm[38].

2.2.6. Downstream processing elements

For ODF formulations,chill rolls and torque winders are used to rapidly cool and collect the extruded fi lm ribbons.The melt comes out from die and fl ow through the wide thin gap,followed by calendaring,in which fi lm is squeezed between two temperature-controlled rotatingrolls.Sometimesdownstream processing elements also play important role in fi nal fi lm appearance and physical properties of fi lm.(A)Effect of calendar temperature on fi lm:Bruce et al.[46]found that when the calendar temperature was too low(chilled to 15°C); fi lms were dif fi cult to stretch resulting in thicker fi lms.On other side, fi lm stuck to the roll when temperature was set at 50°C ormore.Theoptimaltemperaturewasfoundtobe 30°C-35°C.Stretching of fi lms from rolls became harder below optimum temperature range.(B)Effect of distance between the calendaring rolls:The gap between the calendaring rolls is the last in fl uence in shapingthe fi lmbefore it cools into solid form.The gap setting was smaller than the desired fi lm thickness,since the melt was elastic and swelled after emerging from the rolls[46-48].

3. Formulation considerations

Oral strip is ultrathin strip containing an active agent and mainly polymer-plasticizer with desired amount of color, fl avor,sweetening agent and saliva stimulating agents.In HME,glass transition temperature of the polymer plays a decisive role in designing the process parameters.Therefore, rationalized selection of plasticizer is most important according to thermal behavior of polymer and most importantly thermal sensitivity of active[29,49].Sometimes,sugar alcohols,stabilizers,antioxidants,slip agents or anti block agents and anti-sticking agents are added to make the process smooth[50,51].

3.1. Film forming polymers

The choice of an appropriate polymer is crucial for extrusion process.Polymers for hot-melt extrusion(HME)should have the thermoplastic behavior to enable melt extrusion to take place[52,53].They should have a suitable glass transition temperature(Tg)in the range of 50-180°C,low hygroscopicity,stability at extrusion temperature and no toxicity,since large amounts of polymer are used.In this section,polymers which are mainly used in oral strip technology are discussed with special emphasis on thermal stability and extrudability. In HME process,polymer acts satisfactorily with particular plasticizers.Hence,combined discussion of polymer and plasticizer is more appropriate than that of polymer alone.

3.1.1. Polyethylene oxide

Polyethylene oxide(PEO)is a white crystalline hydrophilic powder available in range of 100,000 to 7,000,000 Da molecular weight.PEO is widely accepted fi lm former used in HME because of its broad processing window[54-56].Bruce et al. [46]claimed the use of POLYOX WSR N-10(Molecular weight about 100,000 Da,Dow Chemicals)and POLYOX WSR N-80 (Molecular weight about 200,000 Da,Dow Chemicals).Among all the grades,POLYOX WSR N-10 is most preferred for ODF formulations.Bruce et al.[57]reported extrusion process temperature for PEO is less than 100°C,preferably between 50 and 60°C.So for heat sensitive materials,PEO is advantageous.Theyevaluatedcombinationofhydroxypropylcellulose (HPC)and PEO in different ratios with PEG 400 as plasticizer. Most preferred plasticizer for PEO is vitamin E derivatives. Repka et al.[38]prepared fi lms containing HPC and PEO with andwithoutvitaminETPGS(D-alpha-tocopherylpolyethylene glycol 1000 succinate)as an additive.In addition,the presenceof 3%vitamin E TPGS lowered the Tg over 11°C when compared with the HPC/PEO 50:50 blend fi lm without vitamin E TPGS.Vitamin E TPGS helped in processing of HPC-PEO blends by decreasing melt viscosity and reduction in frictional forces[38,58].Fuisz[59]reporteduse of vitaminE andits derivative as stress crack eliminators during extrusion process.5-10%of vitaminE and its derivatives are most preferred to eliminate the stress cracking of polymer fi lm.

The thermal oxidation of PEO in the solid state has been characterized as an autocatalytic free radical process[60]. Crowley et al.[61]demonstrated different antioxidants like vitamin E and its derivatives,vitamin C(ascorbic acid)and butylated hydroxyanisole(BHA).The addition of 5%vitamin E succinate,1%vitamin E and 30%vitamin E TPGS successfully retarded molecular weight loss of PEO.The color of the extrudates was unchanged.These compounds have previously been found to suppress free radical production in photoirradiated pheolmelanin.In contrast,vitamin C and BHA did notstabilizePEO.BothvitaminEsuccinateandvitaminETPGS decreased the torque during extrusion suggesting an improvement in polymer chain motion.However,BHA and vitamin E acetate were ineffective in stabilizing the molecular weight of PEO during extrusion.Bruce et al.[57]reported that disintegration time of PEO fi lms were increased with increase in moisture content of polymer during long storage period. They hypothesized PEO crystallization in presence of water and this semi-crystalline fi lm would be expected to have a longer disintegration time compared to a non-crystalline amorphous fi lms.

3.1.2. Maltodextrin

Maltodextrin is a polysaccharide synthesized from starch by partial hydrolysis.Maltodextrin is widely accepted due to its low process temperature and high water solubility in ODF prepared by HME.Maltodextrins are classi fi ed by dextrose equivalent(DE)[62,63].Dextrose equivalent is de fi ned as measure of amount of reducing sugars present in relative to dextrose and calculated as percentage on dried basis.As the DE value increases,glucose chains length decreases and the sweetness of themaltodextrinincreases withhigher solubility and the lower heat resistance[64].So,higher DE containing maltodextrins are generally preferred for ODF formulations [65-67].Maltodextrin has miscibility problem with PEG.So, PEG is generally not used with maltodextrin[29].Cilurzo et al. [68]evaluated fi lm forming property of maltodextrins in solvent casting and hot melt extrusion.They used Glucidex IT12 (maltodextrin with DE value12)and the processing temperature throughout the extrusion process was 65-115°C.Glycerol was incorporated as plasticizer to maltodextrin and piroxicam blend with microcrystalline cellulose as anti-sticking agent.

3.1.3. Hydroxypropylcellulose

Hydroxypropylcellulose is a non-ionic water soluble cellulose and combines dual solubility in aqueous and polar organic solvents,thermoplasticity and surface activity with the thickeningandstabilizingpropertiesofotherwatersolublecellulose polymers[69-71].Amongallgrades,KlucelEFandKlucelLFare widely accepted for ODF due to its lower viscosity and lower processing temperature compared to other grades[21,22,72]. Mididoddi et al.[72]mentioned processing temperature for extrusion of HPC Klucel EF and LF was 150-160°C.Mcginity et al.[73]claimed effervescent hot melt extruded polymeric fi lmsprepared withHPCextruded attemperature rangingfrom about 50°C to about 180°C.Fuisz[59]claimed smokeless tobacco fi lm prepared with different concentration of Klucel EF, ELF and LF.3-6%Propylene glycol of total dry weight of formulation was used for successful extrusion of HPC fi lms.

3.1.4. Hydroxypropyl methyl cellulose(HPMC)

Hypromellose(HPMC)ishydrophillic polymer widelyaccepted in ODF prepared by solvent casting but not accepted in fi lms prepared by HME[74-76].The reason for seldom use of HPMC in HME is its glass transition temperature.Tg of hypromellose is 160-210°C and shows degradation in excess of 250°C in signi fi cant amount.HPMC has not so much pronounced difference between Tg and degradation temperature so it is itself a big challenge to extrude the HPMC in such a narrow processing window[58].Incorporation of high amount of plasticizers in fi lm formulations can broaden the processing window of polymer.Aldeman[77]suggested at least 30%w/w plasticizer should be used in successful extrusion of hypromellose.Still less work is done in the area of fi lm forming ability of hypromellose.

3.1.5. Pullulan

Pullulan is most widely used polymer in fi lms prepared by solvent casting method but least used and preferred polymer for HME.Chemically,pullulan is a polysaccharide consisting of maltotriose units and produced from starch by the fungus Aureobasidium pullulans[78].Pullulan is white to off-white tasteless,odorless,non-toxic,non-carcinogenic powder which forms clear transparent fi lm with considerable mechanical strength and it is biodegradable and impermeable to oxygen[79,80].Due to these unique properties,pullulan is widely usedin solventcastingandmanycommercial products [29,81,82].Pullulan starts to decompose at 250°C and chars at 280°C.Due to high melting temperature and narrow processing temperature range,it is less preferred polymer.Fuisz [59]mentioned the use of pullulan with 20-30%of glycerin as plasticizer in hot melt extruded fi lm.

3.1.6. Starch and modi fi ed starch

Starch is considered as good choice as a natural material widely used for extrusion[83,84].Bruce et al.[46]reported the use of starch 1500,a partially pregelatinized starch,in extruded fi lms.They reported poor fi lm formation due to insuf fi cient plasticization initially but optimum plasticization formed thin fi lms with fast disintegration time.Still starch 1500 was considered as poor fi lm former due to stickiness and brittleness in extruded fi lms.

Modi fi ed starches are prepared by physical,enzymatic or chemical treatment of native starch[83].Among these modifi ed starches,hydroxypropyl starch(HP starch)is widely used in ODF preparation[85].Bruce et al.[46]evaluated different modi fi ed starches for their fi lm forming ability as well as rapid disintegration.They evaluated different grades of ready mix modi fi ed starches developed by Roquette pharma,e.g.Lycoat RS 720(higher viscosity HP starch),Lycoat RS 780(lower viscosity HP starch),Lycoat NG 73(pregelatinized HP starch), Lycatab PGS(completely pregelatinized starch),Lab 3455 (pregelatinized HP starch),Nutriose FM06(maize dextrin soluble fi bre)and powdered 400L(modi fi ed corn starch).Plasticizers like glycerin and sugar alcohols were added along with modi fi ed starch for smooth extrusion.Starch containing fi lms havedisintegrationtimehigherthandesired.Sosomeamount ofmodi fi edstarcheswasreplacedwitheither fi llerslikesilicon dioxide,talc,microcrystalline cellulose and titanium dioxide or secondary fi lm forming agent like maltodextrins and PEG 3350.In comparision to fi lm containing alone starch,disintegration was faster and fi lms with lower starch content disintegrate faster(average 17-26 s).The addition of PEG 3350 resulted in shorter disintegration time than addition of maltodextrins.But PEG containing fi lms were brittle and tacky.

3.1.7. Acrylic polymers

Even though less work is done,acrylic polymers like Eudragit have potential for satisfactory fi lm forming ability with HME.Acrylic fi lms prepared by solvent casting and evaporation of isopropyl alcohol showed decrease in plasticity and densi fication of fi lm by evaporation of solvent during storage.This can be eliminated by solvent free HME process[86].Aitken Nichol et al.[87]examined fi lm forming ability of Eudragit E100 with triacetin,polyethylene glycol 6000 and triethyl citrate(TEC)as plasticizer.They reported the stability of Eudragit RS was adequate for extrusion at 130°C.Wu et al.[88]reported smooth extrusion process of Eudragit RSPO at 90-115°C with triethyl citrate as plasticizer.

3.2. Plasticizers

Polymers of high molecular weight exhibit a high melt viscosityandaredif fi culttoextrude.Moreover,ahighTgrequires a high processing temperature,which can degrade sensitive actives.Asageneralrule,anextrusionprocessshouldberunat a temperature 20-40°C above the Tg[89].Polymer properties can be adjusted by the use of plasticizers since these materials reduce the Tg and melt viscosity and also facilitate the extrusion process[90,91].Polymers,their most preferred technical grades,meritsanddemeritsofpolymerandpreferableamount of each plasticizer are summarized in Table 1.

3.3. Sugar alcohols

Sugar alcohols are soluble in water and saliva.Bruce et al.[57] reported that higher amount of sugar alcohols in fi lm formulation can enhance the dissolution by creating porous matrix in strip.Sorbitol,xylitol,mannitol,lactitol,maltitol and erythritol have been reported as sugar alcohols in ODF. Among these all,sorbitol(melting point 95°C)and mannitol (melting point 167°C)are most preferred.

3.4. Antisticking agents

During the extrusion process,high shear force is generated due to frictional forces which ultimately generate excessive heat generation and thermal fl uctuations during process. Addition of antisticking agents like microcrystalline cellulose is most preferred method to eliminate this problem.It is hypothesized that retained moisture by MCC exerts lubricating activity resulting in reduced frictional forces.Cilurzo et al.[68] reported higher disintegration time of piroxicammaltodextrin ODF containing MCC(45 s)as compared to ODF without MCC.Swelling tendency of MCC also retarded dissolution of piroxicam from ODF.

3.5. Sweetening agents

Naturalsweetenerslikeglucoseand fructoseareless preferred in HME due to their charring tendency at high temperature.Sucralose,acesulfame potassium,alitame and neotame are preferred due to its low concentration in total formulation[92].

3.6. Saliva stimulating agents

Saliva stimulating agents are used to increase the rate of production of saliva that would aid the faster disintegration of ODF[29].Citric acid,malic acid,lactic acid,ascorbic acid and tartaric acid are few examples of salivary stimulants.Citric acid has melting point around 100°C and softens at 75°C[93].

3.7. Anti-block agents and fl ow promoters

The anti-block compounds are used to prevent fi lm roll blocking during extrusion cycle.As per the fl ow characteristic of polymer plasticizer blend,required amount of fl ow promoters like silicate derivatives can be added to the formulation[59].

3.8. Flavors and taste masking agents

Incorporation of heat sensitive fl avors is most dif fi cult with ODF prepared by HME.This problem can be eliminated with provision of side stuf fi ng port in barrel as discussed in section 2.2.3[46].Solid dispersion of bitter tasting drugs is reported with hot melt extrusion.Eudragit EPO and ethyl cellulose are some of the widely used polymers that can mask the bitter tasting API by solid dispersion prepared by HME[94,95].

4. Problems found during development and scale up of ODF made by HME

4.1. Die swell phenomenon

The cross section of the fi lm increases upon leaving the die depending upon the viscoelastic property of polymers.So, fi nal dimension of the fi lm changes due to this‘Die swell phenomenon’.Mechanism behind the phenomenon is that polymer is exposed to high shear force and high energy kneading during extrusion.So,polymer comes in state of stress and after completion of extrusion process,polymer triesto come in to relaxation state by increasing theirradius of gyration[38].So,the dimension of fi nal formulation is slightly changed.This problem can be eliminated by slow speed screw operation with slow kneading as well gentle mixing for long time rather than high shear kneading for short duration.

4.2. Fish eye formation

Sometimes due to fl avors or residual moisture in ingredients e.g.natural or phytochemicals products,the blend has inherent tendency to agglomerate.Agglomerate type of uneven,irregular and non-uniform formation in the blend is called‘Fish eye’.Once‘ fi sh eye’or agglomerations are formed, they are extremely dif fi cult to eliminate from the blend.It will create uneven pulsatile fl ow as well as uneven temperature distribution in barrel.To eliminate‘Fish eye’formation in blend,high shear mixing must be employed from beginning. Fuisz[59]reported incorporation of silica derivative e.g.calcium silicate to avoid fi sh eyes in tobacco containing blend.

4.3. Incorporation of liquids with powder blend

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In some cases,liquid ingredients(e.g.plasticizers like PEG,PG and glycerin)are required for smooth extrusion process.First method ofincorporating liquid to polymerblend isgranulation.Cilurzo et al.[68]reported granulation of piroxicam,maltodextrins and MCC blend with glycerol.Bruce et al. [46]reported granulation of PEO with PEG 400 to improve the fl ow.Granulation method can provide uniform mixing and improved fl ow property but it will create multistep processing which is considered uneconomical from industrial aspect. Second method is side stuf fi ng.After molten mass formation inside the barrel,liquid is incorporated via side stuf fi ng port. Bruce et al.[46]reported direct incorporation of PEG 400 into barrel after melting of solid components in compression zone.

4.4. Weight variation within fi lm sheets

Sometimes uneven fi lms are formed due to improper fl ow of powder blend through hopper.So to improve the fl ow propertyofpowerblend,eithergranulationmethodas discussed in section 4.3 or force feeder can be employed.In some cases, glidants are added in dry mix blend.Fuisz[59]claimed the addition of 3-5%silicates to promote the fl ow of tobacco blend containing high moisture content phytochemicals.If weight variation is due to the uneven pulsatile fl ow of molten mass,gear pump provision should be provided near to end of barrel.

4.5. Chemical stability of active during hot melt extrusion

During hot melt extrusion process,many chemical reactions like hydrolysis and solvolysis due to residual moisture and solvent as well as free radical generation are initiated at elevated temperature.To solve the issue of residual moisture and solvent,preheated excipients are sometimes used in process.To eliminate generation of peroxides and free radicals,antioxidants like vitamin E TPGS,butylated hydroxy toluene and butylated hydroxyanisole are generally added to blend[38,42].

4.6. Recrystallization and nucleation of drug molecules

At elevated temperature,pressure and intense mixing,solubility of active in polymer blend is increased but recrystallization of active molecule from the molten blend occurs after temperature drop.This problem can be prevented by preparing highly viscous molten polymer plasticizer medium[38].

5. Development strategies as per quality by design

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Quality by Design(QbD)is a concept outlined by Joseph M. Juran who believed that quality could be planned and that most quality crises and problems related to the way in which quality was planned[96,97].Here hypothetical summary of ondansetron fast dissolving fi lm 25 mg is taken as an example forpharmaceuticaldevelopmentreport illustratingQbD compliant data to FDA.In successive part,introductory discussion covering QTPP,CQA,CMA and CPP are identi fi ed to understand product and process thoroughly.

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(A)Quality target product pro fi le(QTPP):De fi nition as per ICH is “QTPP is a prospective summary ofthe qualitycharacteristics of a drug product that ideally will be achieved to ensure the desired quality,taking into account safety and ef fi cacy of the drug product.”It relates to quality,safety and ef fi cacy,considering e.g.,the route of administration,dosage forms,bioavailability,strength and stability[98,99].Form for identifying QTPP is given in Table 2.

(B)Critical Quality Attributes(CQA):De fi nition as per ICH is“CQA is a physical,chemical,biological,or microbiological property orcharacteristic thatshould be within an appropriate limit,range,or distribution to ensure the desired product quality.”[99-101]CQA for ODF prepared by HME is outlined in Table 3.

(C)Critical Process Parameter(CPP):Parameters of the process that must be maintained in a narrow range to ensure acceptable product quality is called critical process parameters[102]. CPP for hot meltextruded fi lm is given as fl ow diagram in Fig.2.

(D)Critical material attributes(CMA):A physical,chemical, biological and microbiological property of raw material,starting material,reagents,solvents,processing aids,active, packaging and labeling materials that can affect the product throughout its life cycle is considered critical material attributes[99-101].CMA for active used in melt extruded fi lm is enlisted in Table 4.

6. Scale up consideration and dimensional analysis

A chemical engineering is generally concerned with the industrial implementation of hot melt extrusion processes [103,104].HME processes are scale dependent means they behave differently on a small scale and on a large scale.Understandably,formulation scientists have always wanted to fi nd ways of simulating these processes in models to gain insights.So small scale and production scale operation can be simulated[105].

6.1. Dimensional characterization of screw

The design and dimension of the screw within heated barrel has signi fi cant impact on process.The dimension of the screw is given in terms of L/D ratio means length of screw divided by diameter.Typical extrusion process lengths are in the 20 to 40: 1 L/D ratio[44].As per the batch size,18-27 mm extruders in pilot scale and 60 mm extruder in production scale is preferred.Here increase in screw size is approximately 2 folds but extruder output is increased 10 fold at production level by doubling the screw size of pilot scale machine[38].

6.2. Scale-up model calculation and machine selection

6.2.1. Throughput rate calculation

From entry of blend in hopper to fi nal cutting of extruded ribbon in strip form,Scale-up is useful for estimating rates for production in twin-screw extruders[45].For processes that scale-up geometrically,the equation is as follows

Where,Qtarget=Throughput rate in target system(Production scale)(kg/hr),Qreference=Throughput rate in target system (small scale)(kg/hr)and OD=Outer diameter of screw of production scale and small scale extruder

For processes that scale-up volumetrically,the equation is as follows

Where,Qtarget=Throughput rate in target system(Production scale)(kg/hr),Qreference=Throughput rate in target system (small scale)(kg/hr)and SV=Speci fi c volume of production scale and small scale extruder in cc/diameter

6.2.2. Shear rate

Shear rate is de fi ned as the velocity gradient between two surfaces moving at different speeds[45].

Where,D=screw diameter,n=screw speed in rpm and h=over fl ight clearance.

6.2.3. Shear stress

Theshearstressisthemagnitude oftheappliedstressthatthe material experiences as a function of the shear rate and viscosity[45].

6.2.4. Barrel temperature,melt viscosity and mixing ef fi ciency

Barrel temperature is increased or decreased to manage the viscosity of the melt,which impacts the mixing quality. Cooling is often used to raise the viscosity[46].

6.2.5. Speci fi c energy

Speci fi c energy(SE)is de fi ned as the amount of power that is consumed by the motor into each kilogram of material being extruded[45].

6.2.6. Residence time(RT)

The RT provides tentative idea about how long materials are exposed to heat and shear in the process section.Generally extruder residence times are between 5 s and 10 min[45,47].

6.2.7. Temperature shoot-up during pressure generation

Due to very restricted area at die,very high pressure is generated which ultimately create sudden temperature rise [45].The temperature rise is denoted by following equation:

Here,ΔT=change in temperature in°C and ΔP=change in pressure(1 bar=14.503 psi).

7. Conclusion

Thoughsolventcastingiswidelyacceptedmethodby formulation scientist to cast Orodispersible fi lm,hot melt extrusion has immense potential for the same.In this article, common problems found during the scale up and their remedies are thoroughly discussed which will be helpful for voyage of fi lm formulation from lab scale instruments to heavy duty production scale continuous process machines. Till date less work has been done in HME compared to solvent casting but rationalized selection of process and excipients will makes HME as method of choice for ODF formulation in future.

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Rushiraj Jania,b,*,Dasharath Patelb

aSchool of Pharmacy,RK University,Rajkot,Gujarat,IndiabDepartment of Pharmaceutics and Pharmaceutical Technology,Shri Sarvajanik Pharmacy College,Mehsana, Gujarat,India

*Corresponding author.Department of Pharmaceutics and Pharmaceutical Technology,Shri Sarvajanik Pharmacy College,Near-Arvind Baug,Mehsana,384 001,Gujarat,India.Tel.:+91 9712375112.

E-mail address:rushpharma@yahoo.co.in(R.Jani).

Peer review under responsibility of Shenyang Pharmaceutical University.

http://dx.doi.org/10.1016/j.ajps.2015.03.002

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