Spray drying technique: II. Current applications in pharmaceutical technology

Spray Drying Technique: II. Current Applications inPharmaceutical Technology

KRZYSZTOF SOLLOHUB, KRZYSZTOF CAL

Department of Pharmaceutical Technology, Medical University of Gdansk, Hallera 107, 80-416 Gdansk, Poland

Received 27 November 2008; accepted 27 August 2009

Published online 27 October 2009 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21963

Corresponde3183; Fax: þ48-

Journal of Pharm

� 2009 Wiley-Liss

ABSTRACT: This review presents current applications of spray drying in pharmaceu-tical technology. The topics discussed include the obtention of excipients and cospraydried composites, methods for increasing the aqueous solubility and bioavailability ofactive substances, and modified release profiles from spray-dried particles. This reviewalso describes the use of the spray drying technique in the context of biological therapies,such as the spray drying of proteins, inhalable powders, and viable organisms, and themodification of the physical properties of dry plant extracts. � 2009 Wiley-Liss, Inc. and the

American Pharmacists Association J Pharm Sci 99:587–597, 2010

Keywords: spray drying; cospray dryin
g; spray dryers; aqueous solubility; bioavail-ability; modified release; inhalation powders; dry plant extracts
INTRODUCTION

In pharmaceutical technology, spray drying istypically used as a method for removing water orother liquid from the liquid stream. It is also avery important process used for obtaining driedsubstances with distinct properties required forvarious forms of drugs.1–3 The first application ofspray drying in a pharmaceutical setting was toobtain dry extracts of active raw materials fromplants. Spray drying has become popular in thisfield due to the ability to dry even the mostthermolabile fluid extracts without risking thedecomposition of their components. Currently,dry plant extracts are industrially manufacturedalmost exclusively in this fashion. The spraydrying of fluid extracts results in a product withbetter properties compared to other drying

nce to: Krzysztof Cal (Telephone: þ48-58-349-58-349-3190; E-mail: [email protected])

aceutical Sciences, Vol. 99, 587–597 (2010)

, Inc. and the American Pharmacists Association

JOURNAL OF P

methods, since spray drying produces homo-geneous powders. This review presents anddiscusses the current, and, we hope, most inter-esting utilizations in the field of pharmaceuticaltechnology involving the spray drying technique.

EXCIPIENTS AND COSPRAYDRIED COMPOSITES

It has been shown that some of the parametersemployed in spray drying (mainly inlet tempera-ture and the chamber’s internal moisture content)affect the crystalline structure of certain sub-stances, but other process variables, for examplethe inlet and liquid feed rates, are also importantand inter-related. Lactose is a good exampleof this phenomenon, because its compressiveproperties vary after spray drying. Spray-driedlactose was the first substance used to improvethe compression properties of other powders.4

The drying process converts dissolved lactose intoa mixture that is 55–76% crystalline (depending

HARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010 587

588 SOLLOHUB AND CAL

on the drying conditions), and the crystals areconglomerated by an amorphous mass.5 Theunique internal structure of the resulting powderyields a material with better plasticity andbinding during the process of direct tableting.6

The increased plasticity and binding confer theability to obtain tablets of increased hardness andlower friability, but their disintegration time doesnot depend on the compression force used tomanufacture the tablets. This kind of lactose iscommercially available as Tabletose.

The effect of spray drying on mixtures of drugsubstances and various types of excipients withrespect to direct tableting ability has been asubject of extensive studies in recent years. Directtableting is desirable to drug manufacturersbecause a powder, which is suitable for directtableting, does not require further processing(physical or chemical) to create tablets. This isdesirable from an economical perspective, but italso improves process performance and facilitatesthe control of the drug under cGMP requirements.There are several commercially available mix-tures that are designed for direct compression,such as Ludipress (a-lactose monohydrate, poly-vinyl pyrrolidone, and crospovidon), Cel-O-Cal(cellulose, calcium phosphate), and Microclac 100(a cospray dried microcrystalline cellulose andlactose monohydrate). These mixtures requireonly a thorough mixing with the drug substanceand other excipients. Solutions or suspensionsof active substances and excipients that can bespray-dried and then directly tableted are cur-rently being sought.7

Low molecular mass sugars are difficult toprocess by spray drying. Frequently, conditionsthat occur in the spray dryer chamber cause thesekinds of excipients to form glassy state depositson the chamber walls. This results in low yield,extended viscosity of the dried product and itsfurther hygroscopicity. There is no fully effectiveway to overcome these difficulties. In practice, thehighest viscosity of a glassy formation is reached10–208C above glass transition temperature (Tg).That leads to the conclusion that the temperatureof the particle surface should be under thattemperature to prevent extensive deposit forma-tion and product loss.8 In general, a temperatureof drying that is 108C below Tg seems to be safe;however, Tg for low molecular mass sugars is solow that it is very difficult to maintain a costeffective dried product. The next way to deal withthe problem is to add high molecular massexcipients, for example, maltodextrin to raise

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010

Tg. It is effective in a predictable way for binarymixtures (sugar–maltodextrin), but for morecomplex mixtures (sugar–sugar–maltodextrin) itis difficult to predict how high Tg will be. Additionof polymers is not always possible. Intensivestudies were performed to develop a single stagecospray dried formulation (dried from one com-plex feed) for direct compression containingparacetamol and carbohydrates. Despite theabove difficulties, the spray drying process gavepowders of good flowability and improved tablet-ing ability, which resulted in tablets with goodtensile strength,7 and the quantitative optimiza-tion of these powders was carried out with useof statistical methods.9 The powders producedshowed good rheological properties, and theircompression resulted in tablets with satisfactoryproperties (e.g., friability, disintegration time,and tensile strength). Importantly, studies showedthat the quantitative composition of the feedsubjected to spray drying had no influence oneither the process’s efficiency or the final moisturecontent in the powder. Based on these findings,formulations containing paracetamol or ibuprofenand adequate amounts of carbohydrates werespray dried on industrial scale. The resulting drypowders were also ready for direct compres-sion.10,11 These studies are of great importancebecause, by using popular active substances, theauthors successfully scaled up the process from alaboratory scale to an industrial scale, which isdifficult in spray drying. This demonstrates thatthe implementation of spray drying to drugs’manufacture can be very profitable. Also, the useof statistical methods in successfully designing aformulation was validated.

It is also possible to change the melting point ofan active substance by spray drying, to avoid hotspots (points of spontaneous recrystallization,which appear under the high pressure in thepunches) that affect the tablets’ properties.Alginate–lactose coated trandolapril particlesprepared by spray drying had a higher meltingpoint and showed no differences in solubilityprofile relative to the parent crystals.12

INCREASING THE AQUEOUS SOLUBILITYAND BIOAVAILABILITY OF ACTIVESUBSTANCES

The next goal for the technique of cospray dryingof active substances with excipients is to increasethe drug’s aqueous solubility. This issue is of

DOI 10.1002/jps

SPRAY DRYING TECHNIQUE: II 589

importance because about 40% of new activesubstances have low solubility in water.13,14

Increasing the aqueous solubility of a drug canhelp in the development of new therapeuticmethods. Moreover, approximately half of newdrugs cause problems during their formulationprocess, and fail to became marketed products dueto issues related to their high lipophilicity (e.g.,low aqueous solubility, low/unrepeatable bioavail-ability, difficulties in administration).14 The mostfrequently used method for increasing the aqu-eous solubility of an active substance is to reduceits particle size, thus increasing the surface areain contact with the solvent.14 While this methodis relatively easy to execute and cost-effective, it isnot always effective and desirable.15 The simplestway to reduce a substance’s particle size is tomicronize the substance, using various typesof mills, but this deprives the manufacturer ofcontrol over particle properties, such as morphol-ogy and surface features. Additionally, grindingin mills can change the crystalline form of thesubstance, because it is a high-energy process,which can disturb the formulation process andnegatively affect the stability of the final drug.Spray drying is another way to produce/createparticles with reduced size and to control particlesize and morphology if the material is dried froma solution. In addition, it allows for control ofthe particle’s properties. One example of this isartemisinin, a poorly water-soluble drug that hasbeen spray dried with different ratios of mal-todextrin and under different process parameters.The aqueous solubility of the cospray-driedmaterial was related distinctly to process para-meters like inlet temperature, concentration infeed, and flow rate, which have the most influenceon the particle characteristics responsible forsolubility (e.g., particle size and crystallinityrate).16 These relationships can be limiting factorsin the reproducibility of the process and itsscale up.

A study on grizeofulvin provides a particularlyvaluable example of the use of cospray drying toincrease aqueous solubility and bioavailability.17

Grizeofulvin, either alone or with the additionof 0.05% Poloxamer 407, was spray dried fromorganic solutions using a laboratory dryer. Thepowders obtained were encapsulated into gelatincapsules and orally administered to rats. Thestudy revealed that the active substance spraydried in combination with a surfactant had bettersolubility and bioavailability (6.92mg/mL h� 1.98%compared to 3.94mg/mL h� 1.04% for the control

DOI 10.1002/jps JOUR

formulation). The solubility of a pure substanceafter being subjected to spray drying was alsohigher than the control. However, the pure spray-dried substance’s absorption did not changesignificantly from that of the unmodified sub-stance. Analysis of the particles’ morphologyrevealed that particle size is not the only factoraffecting the solubility and absorption of thesubstance. The addition of the surfactant resultedin increased particle size, but absorption wasimproved due to the increased wetability of theparticles. The surfactant used was the least toxicamong synthetic surfactants and was described asbiocompatible (having no adverse effects after oraladministration). A similar study was performedon itraconazole. This drug, which has poor watersolubility, was subjected to spray drying withsurfactants (poloxamer 188, poloxamer 407) inorder to achieve a dry powder capable of beingredispersed into a stable nanosuspension. Furtherstudy also showed improved solubility for itraco-nazole from a redispersed nanosuspension.18

The simultaneous codrying of a water-insolubledrug (flurbiprofen) with a water-soluble substance(sodium salicylate) is another example of anexperiment aimed at increasing the aqueoussolubility of active substances. The simultaneoussupply of an ethanolic solution and a watersolution occurred through a four-fluid nozzle.The composite particles obtained showed higherflurbiprofen release relative to the pure form. Thestudy’s conclusion states that the improveddissolution rate of the flurbiprofen was a surfaceeffect resulting from the rapidly dissolving sodiumsalicylate.19 The cospray drying of curcuminwith PVP gave a solid dispersion with a highercurcumin dissolution rate than a physical mixtureof these substances. Spray drying caused thecurcumin to convert from a crystalline form into amore soluble amorphous form, and PVP increasedthe viscosity and disabled the migration of themolecules to constitute a crystalline form.20

Increased bioavailability was also reported forpiroxicam, which had been microencapsulatedinto gelatin shells by spray drying.21

Self-emulsifying drug delivery systems havebeen the subject of extensive studies recently.These systems are produced by the removal ofwater from oil-in-water emulsions, followed by theemulsion’s reconstitution via the addition of waterex tempore. During the water removal phase, thematrix substance surrounds the oil phase formingthe emulsion, whose size depends on the size ofthe oily phase’s droplets. This increases these

NAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010


systems’ stability because they may be stored inthe dry form. It also facilitates the use of smalleramounts of surfactant for stabilization purposes.An emulsion containing the anticancer agent5-PDTT, which has limited aqueous solubility,maltodextrine as a matrix material, sodiumcaseinate as an emulsifier, and Miglyol 812 asan oily phase, has been the subject of suchstudies.22 Spray-dried powders of this mixturewere subjected to dissolution and bioavailabilitystudies, which revealed a good release andincreased bioavailability of the active substancefrom this drug form.

A formulation with nimodipine was also createdin a similar way. It was shown that there were nosignificant differences in bioavailability betweenthe liquid and spray-dried (and redispersed)microemulsions. Both of these microemulsionswere characterized by higher bioavailability whencompared to traditional tablets.23 Studies on self-emulsifying drug delivery systems demonstratedtheir ability to remain stable as dry powdersand highly redispersible forms, as well as theirsuperiority to conventional drug forms. Self-emulsifying drug delivery systems have theirplace in further research to increase the aqueoussolubility and bioavailability of active substances.Spray drying clearly gives desirable propertieslike achieving stable dispersions for both emulsionand suspension type formulations. Studies onnew formulations are valuable not only in termsof new scientific achievement but also as amethod for comparing these formulations withwell-established products, and possibly replacingthem. Solid-state emulsions prepared by spraydrying can also be used as a protective agentfor drug substances that are unstable in thegastrointestinal tract.24

MODIFIED RELEASE FROM SPRAYDRIED PARTICLES

Spray drying may be a useful tool for theproduction of modified or delayed release parti-cles. The attempt to produce microcapsulescontaining vitamin C targeted for release in thecolon is an example of such studies.25 Methacry-late polymers, specifically Eudragit RL, RS, andL, were used to coat the active substance. Theauthors did succeed in generating a releaseindependent of the drug’s concentration butdependent on the polymer’s solubility at a givenpH.


Subjecting a water-in-oil emulsion to spraydrying results in a water phase coated by thepolymer dissolved in the oily phase. There arewell-documented studies in which vancomycinwas dissolved in a water phase and in which acopolymer of lactic acid and glycolic acid wasdissolved in the outer organic phase, and theemulsion was spray dried.26 This resulted in arather poor yield (50% of solids) but good particleforming efficiency (up to 99% of the particlesincorporated the drug). The particles formed wereof an appropriate size for administration into theeye as a suspension (particle size under 11mm).In vitro and in vivo studies demonstrated thepossibility of modifying vancomycin’s release bychanging the polymer–vancomycin ratio used inthe process. The formulation studied had agreater bioavailability (AUCrel¼ 2.31) comparedto a vancomycin-containing solution. Addition-ally, no significant effect from hypromelose-mediated stabilization on the bioavailability ofthe vancomycin administered as a suspension wasobserved. The studied spray-dried emulsion wasnot stabilized with surfactants. On an industrialscale, this may cause delamination, while theaddition of a surfactant may alter the releaseprofile and behavior of the mixture during spraydrying. The addition of a biocompatible surfactantmight not be strong enough to stabilize this form.Spray drying ketotifen with polymers similarto those mentioned above yielded microspheredelivery systems appropriate for intraperitonealimplantation. Following in vivo implantation,ketotifen release from the microspheres wasdetected in the plasma after about 350 h.27

The ability to modify an active substance’srelease from tablets dry coated with a cospraydried powder containing lactose, sodium alginate,and chitosan has been demonstrated.28 Thechange in the release rate was dependent onthe coating-powder’s method of preparation; andthe simple mixing of lactose with a sodiumalginate–chitosan complex did not result in analtered release. The cospray-dried powder usedfor dry coating was characterized by goodcompression and rheological properties. Tabletscoated with this powder had good acid-resistanceand a prolonged period of slight release, whichwas followed by the distinct eruption of the drugsubstance. The ability to control the delayedrelease based on the composition of the coatingwas demonstrated. Thus, it seems possible thatspray drying will emerge as a tool for theproduction of all tablet components.

DOI 10.1002/jps


Due to its unique properties, chitosan is aninteresting but sometimes difficult subject ofstudy with respect to controlled release fromvarious types of microparticles, for example,attempts to encapsulate vitamin C by spraydrying it with cross-linked chitosan.29 However,these attempts did not result in a significantlydelayed release. It is important that microcap-sules with good physical properties and stabilitywere produced, which suggests that follow-upstudies in this field would be valuable. The use ofchitosan as a matrix for paracetamol has also beenstudied. Microspheres obtained by spray dryinghave demonstrated markedly delayed release(although not in all concentration ratios). Thetransformation of paracetamol into its amorphousform and its ability to bind to chitosan viahydrogen bonds has also been demonstrated.30

Similar results were obtained using differentequipment for particle preparation, for example,the use of a four fluid nozzle.31 These results showthat active ingredient–carrier hydrogen bondingcannot give properly delayed release. Chitosan/b-cyclodextrin microspheres loaded with theo-phylline were found to be able to sustain release atlow pH, but only 60% of the encapsulated drugwas released after 8 h.32

SPRAY DRYING OF PROTEINS

Biopharmaceuticals in the solid state are char-acterized by higher stability than the samesubstances in solution. Due to this, they may bestored under milder conditions without fear ofpossible decomposition or disintegration. Fora long time, lyophilization has been the mostpopular method for the production of proteinpowders. Such products are usually used forparenteral administration following dissolution.The lyophilization takes place in the final vessel,and only the powder’s solubility is important.Nevertheless, if a fine and flowable powder isrequired, another process must be employed tobreak-up the lyophilizate. Such a secondaryprocess significantly reduces the efficacy of thewhole operation and deprives the operator ofcontrol over the properties of the particlesgenerated.

As biotechnology has advanced, the need fornew methods of protein drying has emerged.Spray drying seems to be the most suitable,mainly due to the protective character of theprocess of the solvent removal from the material


subjected to drying. Studies have revealed, how-ever, that there are many serious problemsrelated to this method. One of the basic problemslies in the low process efficacy achieved in themost frequently used laboratory spray dryers. Inarticles where the efficacy is mentioned, it doesnot exceed 50%.33 This is undesirable not onlyfrom an economic point of view but also from theperspective that overall research progress isimpeded, since less product means fewer analyses.Laboratory spray dryers are the smallest avail-able and allow for the recovery of only a limitedamount of substances from the feed. The process-related costs and the availability of proteinproducts also remain significant problems.

Maury et al.33 have focused on this issue. Theirstudies were conducted with trehalose, a majorcarbohydrate used as a carrier in protein for-mulations intended for spray drying. It was foundthat the commercial cyclones used in laboratoryspray dryers are not able to catch particles smallerthan 2mm, which may have a significant effecton the efficiency of the protein drying process.The authors described a cyclone with differentdimensions and demonstrated its superiority.Inappropriate adjustments to the process’s con-ditions are another potential factor affectingthe process efficiency. It is known that processefficiency is heavily dependent on the Tinlet/Toutlet

ratio. No significant effect from the nozzleparameters or the drying air flow rate (althoughthe use of the greatest flow rate possible isrecommended) has been observed. Prinn et al.34

used statistical analysis to show that, to obtaina balance between yield and particle size, it isnecessary to balance the solid content in the liquidstream and the feed rate.

Intensive studies have allowed the identifica-tion of threats to protein particles during spraydrying. Although the risk of thermal denaturationis negligible, proteins often do denature dueto dehydration. Thus, it is necessary to supplysubstances capable of replacing the hydrogenbonding that exists in an aqueous environment(e.g., trehalose). Omitting the protecting sub-stances may lead to disorders in, or the destruc-tion of, a protein’s secondary structure, thusleading to its deactivation. During spray drying,the large particles may be subjected to shearingtension during atomization at the phase (air–water) boundary. Studies have revealed thatthe process of atomization itself does not producesufficient tension in particles. Nevertheless,the forces acting upon the droplet-air phase



boundaries during rapid evaporation of solventare large enough to damage certain sensitiveproteins. Recombinant human growth hormone(rhGH) and bovine albumin are examples of suchsensitive proteins.

The next undesirable process occurs at thephase boundary during the drying process.Particles may undergo aggregation due to shearstress from the air–water interface and produceboth soluble and insoluble aggregates. Thisprocess can account for some of the denaturation,since aggregation occurs after protein unfolding.It has been shown that adding Zn2þ (associateswith protein to form a dimer) and polysorbate 20can help prevent the formation of soluble andinsoluble particle conglomerates, respectively, inthe case of rhGH.35,36 Other studies have shownthat drying rhGH in the presence of the above-mentioned substances results in the formation ofparticles with properties suitable for subsequentadministration via the respiratory tract.37 It isexpected that such sets of protecting substancesshould be effective in aiding other potentiallysensitive substances.38

The degree of denaturation on the phase borderalso depends on the contact area. This is asignificant problem due to excessive surface areaof the phase boundary (60,000 m2/m3 of 100mmdroplets).1 Maury et al.33 suggest the use of alonger chamber manufactured specifically for thispurpose, which will allow for an increase in thedroplet size and thus a decrease in the dispersion’ssurface area, without losing material on thechamber walls. This is necessary in order tooperate on a laboratory scale, as the amount ofmaterial at the disposal of an investigator is rarelysufficient for larger dryers, mainly due to the costof producing the substance. The studies indicatethe possibility that the morphology of particlesmay be manipulated by changing the solid’sconcentration in feed, Tinlet, and the content ofthe protecting substances (low molecular weightsugars are problematic due to their propensity tobe involved in glassy state deposits). The difficul-ties related to the formation of glassy deposits ofthe amorphous protecting substances on the dryerwalls have not yet been completely resolved.

INHALATION POWDERS AND VACCINES

Spray drying is often used to produce proteinpowders designed for administration via therespiratory tract. The resulting particles are of


appropriate shape and size to allow for a homo-geneous dispersion of aerodynamic propertiesenabling the particles to reach deep into thebronchial tree. While it is obvious that a powderdesigned for such a purpose must retain itsactivity, it is also important that it not changeits aerodynamic properties during storage. In thecase of an IgG1 antibody formulation spray-driedwith mannitol, trehalose, saccharose, and iso-leucine and subsequently vacuum dried, it wasdemonstrated that these substances increase thestability of the stored protein powders andenhance their intrinsic properties.39 However,excipients also have their own properties that caninterfere with a drug’s formulation properties.Costantino et al.40 conducted a study on theinfluence of the crystalline form of mannitol,which is used as a stabilizing agent for an anti-IgEsynthetic monoclonal antibody. It was shown thatmannitol’s ability to crystallize spontaneously hasa great influence on the stability of the driedprotein, because it limits stability of protein andaerosolization performance. Continuing this lineof exploration, Andya et al.41 performed studies onthe influence of other excipients in the process ofspray drying to create a stable dry protein powderfor pulmonary delivery. Those studies show thecomplexity of formulating a dry protein powder,not only in terms of avoiding protein degradation,but also in terms of ensuring that the final productis an inhalable powder. Similar investigationsinto rhGH are discussed above.37 The most recentstudies show that it is possible to obtain stable drypowders for gene delivery by spray drying. Thespray dried powders had good aerodynamicproperties (no agglomeration occurred, cohesiveforces between particles had no influence) andstability, while the spray drying process resultedin an acceptable yield of >45%.42

Respiratory antimicrobial agents, especially incombined forms, would be very valuable. Previousstudies have shown that spray drying a liquidstream containing doxycycline and ciprofloxacinmight produce a dry powder with appropriateaerodynamic properties and greater physicalstability than the analogous single spray-driedsubstance.43

The potential for creating respiratory particlesby spray drying has some problems that mustbe addressed. The morphology of spray-driedparticles is very important and depends on manyvariables. Darbandi et al.44 showed that theability to create rifampicin particles for inhalationdepends on the vehicle in which the spray drying

DOI 10.1002/jps


occurs. O’Hara and Hickey45 showed data onthe manufacture and properties of a new form ofrespiratorily administered rifampicin-loadedPLGA microspheres. They concluded that spraydrying is a superior method to manage solventevaporation and to obtain inhalable microspheres,although in vivo studies are still necessary.Maltesen et al.46 described the process variablesinfluencing spray-dried insulin intended forrespiratory delivery.

A valuable comparison of two important tech-niques used in the preparation of inhalableparticles, namely, jet milling and spray drying,was presented by Louey et al.47 Both techniquesproduce very small particles of similar size, butwith different morphological properties. Spraydrying produced a powder with greater aerosoldispersion.

Successful spray drying of protein leads tothe possibility of producing vaccines intendedfor respiratory administration. Vaccines mustremain active after drying, physicochemicallystable, and ready for aerosolization. It is knownthat it may be possible to produce active nonviralpowders intended for inhalation.42 The formula-tion and particle engineering aspects of preparingan inhalable dry powder vaccine containing liveattenuated Newcastle virus were studied exten-sively.48 It was shown that the addition of selectedstabilizing agents results in the possibility ofproducing a vaccine suitable for mass vaccination.Further in vivo studies have shown that obtainedvaccine is immunologically active.49 Bacterialpowders can also be used for the production ofimmunizing agents. A vaccine for tuberculosiswas successfully formulated on a laboratory spraydryer. The vaccine produced sustained 60% of itsCFUs and remained relatively stable up to 56 daysunder accelerated stability test conditions.50

These reports show good prospects for the marketimplementation of inhalable vaccines. As amodification of the basic spray drying process,spray freezing should also be mentioned. Studiesshow that the influenza vaccine produced by sprayfreezing was appropriate for respiratory deliveryand gave an even more successful immunizationthan the traditional intramuscular vaccine.51 Itis possible that future studies will show similarprospects for spray-dried powders.

SPRAY DRYING OF VIABLE ORGANISMS

Although studies on the drying of microorganismsare usually investigating their utility as a food


source, they are of potential interest as apharmaceutical technology. The pharmaceuticalindustry utilizes many viable organisms as‘‘producers’’ of various biologically active sub-stances or intermediate compounds used to makeactive substances. Yeasts are utilized mainly asbiocatalysts for various chemical reactions, andtheir availability in powder form facilitates theirapplication and storage and prolongs theirviability. In addition, knowledge concerning thebehavior of bacteria under spray drying condi-tions is important, not only due to the possibilitythat dried mixtures may be contaminated bypathogenic organisms but also due to the gradu-ally increasing significance of probiotic bacteria.

Studies have revealed that it is possible toadjust the mixture composition and spray dryingconditions in such a way that dry powders orcondensed suspensions of microorganisms can beobtained. This is not an easy task, since severalmechanisms of bacterial cell damage occur duringthe spray drying process. These mechanisms arenot exclusively due to temperature, and some ofthem are triggered by the rapid removal of water.What’s more, these mechanisms occur not only atthe level of the cellular membrane but also at thelevel of DNA and ribosomes.52,53

In pharmaceutical manufacturing, the micro-biological purity of the resultant products is of theutmost importance. Another advantage of spraydrying is that it can be set up as an aseptic process.The use of HEPA filters on the drying andatomizing air, sterilization of the nozzle andchamber walls, and fast product collection ensuresthe sterility of the product. Since the entire dryeris manufactured from high-quality materials andall wire connections are as short and as straight aspossible, sterilization is usually carried out withsuperheated steam.54 However; aseptic manufac-turing via spray drying is a very rare solution dueto a lot of specific engineering and high cost, andthus most spray-dried products are sterilizedseparately when necessary.

MODIFYING THE PROPERTIES OF DRYPLANT EXTRACTS DESIGNED FORTABLETING OR ENCAPSULATION

As mentioned, plant dry extracts are commonlyobtained by the spray drying technique. Theparticles formed by this method are characterizedby high hygroscopicity and viscosity, low flow-ability, and poor suitability for tableting or



encapsulation. Their hygroscopic nature resultsin lowered stability (either physical or chemical)and the need for special storage conditions. It alsoaffects the powder’s viscosity, which in turndetermines its flowability. Nevertheless, the maincause of the powder’s low flowability is the smallsize of its particles, which is common with spray-dried extracts. The small size results in problemsrelated to the powder’s transport on an industrialscale, where uniform mass flow out of bins andother vessels is required. In the case of dry plantextracts, the interactions between the powderparticles are often so strong that they do not pourat all. This phenomenon may also generateproblems related to obtaining proper mass uni-formity in solid dosage forms. In addition, thetablet manufacturing process requires the appli-cation of high pressure, which in turn results intablets that are too hard and give prolongeddisintegration times.55 A free-flowing powder ismuch more important for encapsulation. Themechanism of capsule filling requires the abilityto separate small doses of powder from the bulk.The homogeneity of the doses depends on theabovementioned properties to a much greaterextent than it does for tablets.56

It is important to differentiate between therheological properties of the powder and itsflowability. The rheological properties dependon the physicochemical properties of the powderand can only change by modification of thesephysicochemical properties. Flowability, on theother hand, is dependent on the type of surfaceupon which the pouring of the powder takesplace. The smaller the dry extract’s particles,the greater the number of problems related topowder pouring. Therefore, attempts have beenmade to agglomerate the dry plant extractsin order to improve these properties. The produc-tion of agglomerates (wet or dry granulation) isa generally accepted method for improving theflowability and compression properties of dryplant extracts.57,58

The problem with plant extract granulation liesin granules’ heterogeneity. The number of com-ponents in the extract makes it difficult to produceidentical agglomerates with every repetition;thus, it is difficult to achieve dose uniformity.Furthermore, the stability of many of the activeingredients is unknown. Wet granulation usingwater is not advisable. Thus, it is difficult to adjustthe conditions under which the granulation andthe subsequent granulate drying should occur,and it is difficult to select a suitable binding agent.


To ameliorate these problems, researchers haveattempted granulation using Eudragit E inacetone solution. A granulate with a less hygro-scopic nature and better rheological propertieswas obtained.57 An attempt to granulate dryMaytenus ilicifolia extract after the addition ofAerosil as a protecting substance, and eithersodium crosscarmelose or microcrystalline cellu-lose as granulating substances, resulted in similareffects.58

The composition of plant extracts is anothercause of difficulties during the spray dryingprocess. Extracts contain many ingredients thatdemonstrate high viscosity under spray dryingconditions (e.g., low molecular-weight sugars andorganic acids), which results in an increasedtendency to leave undried material deposits onthe chamber walls.59 This, in turn, disrupts thechamber’s hydrodynamics and hinders the com-plete drying of the product. Plant extracts aretherefore usually spray dried together withcarrier substances intended to facilitate thedrying process. Because some of the problemsencountered in spray drying plant extracts resultfrom the surface properties of the powder parti-cles, encapsulation by cospray drying might behelpful. Su et al.60 were able to create stablemicrocapsules from specially prepared nanopar-ticles of a dry plant extract with good efficiency.

SUMMARY

The range of applications presented in this paperdoes not exhaust the subject of spray drying inpharmaceutical technology. The possibilities arenumerous, and they have not yet been fullyexplored by the pharmaceutical industry. Therapid development of research aimed at extendingthe application of spray drying, as well as morefrequent attempts to incorporate the newesttechnologies into production, is expected. Theliterature data suggest that the most popularareas of interest lie in the study of protein drugs,anticancer substances, improvements in the aqu-eous solubility of active substances, and in manyother fields that are very important for modernpharmaceutical technology.

Spray drying can successfully replace lyophili-zation in the manufacturing of parenteral drugs;and the spray-dried products have the advantageof being fine and free-flowing powders, in contrastto lyophilizates. Novel spray-dried forms, such

DOI 10.1002/jps


as nanosuspensions, microemulsions, and micro-spheres are awaiting utilization in commercialproducts. Spray-dried self-emulsifying drug deliv-ery systems for oral administration are beingdeveloped. The inexpensive, rapidly deployed andeasily administered via injection room tempera-ture stable spray dried vaccines, which can beuse in the case of global epidemic, are a greatchallenge and matter of the near future.

Spray drying is an energy-intensive process,and the costs of installation and maintenance arealso relatively high.61 In addition, the develop-ment of broadly adoptable methods is very cost-intensive. The great problem associated withspray drying, mainly drying of proteins, thatmust be solved is the transfer and scale up ofthe process according to the cGMP requirementsof the pharmaceutical industry. It will be anexpensive and difficult challenge because thereare no strict guidelines and examples regardingthis process, and often trial and error is the onlyway to proceed. Nevertheless, the speed anddirection of developments in the field of drugadministration studies will elucidate the need forthe development of spray drying techniques in thepharmaceutical industry.

REFERENCES

1. Masters K. 2002. Spray drying in practice. Char-lottenlund: SprayDryConsult International ApS.

2. Vehring R. 2008. Pharmaceutical particle engineer-ing via spray drying. Pharm Res 25:999–1022.

3. Parikh DM. 2008. Advances in spray drying tech-nology: New applications for a proven process. AmPharm Rev. Volume 11, issue 1.

4. Takeuchi H, Yasuji T, Hino T, Yamamoto H, Kawa-shima Y. 1998. Spray-dried composite particles oflactose and sodium alginate for direct tableting andcontrolled releasing. Int J Pharm 174:91–100.

5. Chiou D, Langrish TAG, Braham R. 2008. The effectof temperature on the crystallinity of lactose pow-ders produced by spray drying. J Food Eng 86:288–293.

6. Gohel MC, Jogani PD. 2005. A review of co-processed directly compressive excipents. J PharmPharmaceut Sci 8:76–93.

7. Gonnissen Y, Remon JP, Vervaet C. 2007. Develop-ment of directly compressive powders via co-spraydrying. Eur J Pharm Biopharm 67:220–226.

8. Bhandari BR, Howes T. 1999. Implication of glasstransition for the drying and stability of dried foods.J Food Eng 40:71–79.

9. Gonnissen Y, Goncalves SI, Remon JP, Vervaet C.2008. Mixture design applied to optimize a directly


compressive powder produced by cospray drying.Drug Dev Ind Pharm 34:248–257.

10. Gonnissen Y, Goncalves SIV, De Geest BG, RemonJP, Vervaet C. 2008. Process design applied tooptimize a directly compressible powder via contin-uous manufacturing process. Eur J Pharm Bio-pharm 68:760–770.

11. Gonnissen Y, Verhoeven E, Peeters E, Remon JP,Vervaet C. 2008. Coprocessing via spray drying as aformulation platform to improve the compactabilityof various drugs. Eur J Pharm Biopharm 69:320–334.

12. Makai Z, Bajdik J, Eros I, Pintye-Hodi K. 2008.Evaluation of the effect of lactose on the surfaceproperties of alginate coated trandolapril particlesprepared by spray drying. Carbohydrate Polym 74:712–716.

13. Tang B, Cheng G, Gu JC, Xu CH. 2008. Develop-ment of solid self-emulsifying drug delivery sys-tems: Preparation techniques and dosage forms.Drug Discov Today 13:606–612.

14. Gursoy RN, Benita S. 2004. Self-emulsifying drugdelivery systems (SEDDS) for improved oral deliv-ery of lipophilic drug. Biomed Phamacother 58:173–182.

15. Serajuddin ATM. 1999. Solid dispersion of poorlywater-soluble drugs: Early promises, subsequentproblems, and recent breakthroughs. J Pharm Sci88:1058–1066.

16. Sahoo NG, Abbas A, Judeh Z, Li CM, Yuen KH.2009. Solubility enhancement of a poorly water-soluble anti-malarial drug: Experimental designand use of a modified multifluid nozzle pilot spraydrier. J Pharm Sci 98:281–296.

17. Wong SM, Kellaway IW, Murdan S. 2006. Enhance-ment of the dissolution rate and oral absorption of apoorly water soluble drug by formation of surfac-tant-containing microparticles. Int J Pharm 317:61–68.

18. Chaubal MV, Popescu C. 2008. Conversion of nano-suspensions into dry powders by spray drying: Acase study. Pharm Res 25:2302–2308.

19. Ozeki T, Beppu S, Mizoe T, Takashima Y, Yuasa H,Okada H. 2006. Preparation of polymeric sub-micron particle-containing microparticles using4-fluid spray drier. Pharm Res 23:177–183.

20. Paradkar A, Ambike AA, Jadhav BK, Mahadik KR.2004. Characterization of curcumin-PVP solid dis-persion obtained by spray drying. Int J Pharm 271:281–286.

21. Piao MG, Yang CW, Li DX, Kim JO, Jang KY, YooBK, Kim JA, Woo JS, Lyoo WS, Han SS, Lee YB,Kim DD, Yong CS, Choi HG. 2008. Preparationand in vivo evaluation of piroxicam-loaded gelatinmicrocapsule by spray drying technique. BiolPharm Bull 31:1284–1287.

22. Dollo G, Le Corre P, Guerin A, Chevanne F, BurgotJL, Leverge R. 2003. Spray dried oil-in-water emul-sion to improve oral bioavailability of poorly solubledrugs. Eur J Pharm Sci 19:273–280.



23. Yi T, Wan J, Xu H, Yang X. 2008. A new solid self-microemulsifying formulation prepared by spraydrying of poorly water soluble drugs. Eur J PharmBiopharm 70:439–444.

24. Ge Z, Zhang XX, Gan L, Gan Y. 2008. Redispersible,dry emulsion of lovastatin protects against intest-inal metabolism and improves bioavailability. ActaPharmacol Sin 29:990–997.

25. Eposito E, Cervellati F, Menegatti E, Nastruzzi C,Cortesi R. 2002. Spray dried Eudragit microparti-cles as encapsulation devices for vitamin C. Int JPharm 242:329–334.

26. Gavini E, Chetoni P, Cossu M, Alvarez MG, Saet-tone MF, Giunchedi P. 2004. PGLA microspheresfor the ocular delivery of a peptide drug, vancomy-cin using emulsification/spray-drying as the pre-paration method: In vitro/in vivo studies. Eur JPharm Biopharm 57:207–212.

27. Guerrero S, Muniz E, Teijon C, Olmo R, Teijon JM,Blanco MD. 2008. Ketotifen loaded microspheresprepared by spray-drying poly(D,L-lactide) andpoly(D,L-lactide-co-glycolide) polymers: Character-ization and in vivo evaluation. J Pharm Sci 97:3153–3169.

28. Takeuchi H, Yasuji T, Yamamoto H, Kawashima Y.1999. Spray-dried lactose particles containing anion complex of alginate-chitosan for designinga dry-coated tablet containing a time-controlledreleasing function. Pharm Res 17:92–100.

29. Desai KGH, Park HJ. 2005. Encapsulation of vita-min C in triphosphate linked chitosan microspheresby spray drying. J Microencaps 22:179–192.

30. Takahashi H, Chen R, Okamoto H, Danjo K. 2005.Acetaminophen particle design using chitosan anda spray-drying technique. Chem Pharm Bull 53:37–41.

31. Chen R, Okamoto H, Danjo K. 2006. Particle designusing a 4-fluid-nozzle spray-drying technique forsustained release of acetaminophen. Chem PharmBull 54:948–953.

32. Zhang WF, Chen XG, Li PW, He QZ, Zhou YH.2008. Preparation and characterization of theo-phylline loaded chitosan/b-cyclodextrin micro-spheres. J Mater Sci: Mater Med 19:305–310.

33. Maury M, Murphy K, Kumar S, Shi L, Lee G. 2005.Effect of process variables on the powder yield ofspray dried trehalose on a laboratory spray-drier.Eur J Pharm Biopharm 59:565–573.

34. Prinn KB, Costantino HR, Tracy M. 2002. Statis-tical modeling of protein spray drying at lab scale.AAPS PharmSciTech 3:article 4.

35. Ameri M, Maa YF. 2006. Spray drying of biophar-maceuticals: Stability and process considerations.Drying Technol 24:763–768.

36. Maa YF, Nguyen PA, Whu SW. 2008. Spray-dryingof air-liquid interface sensitive recombinant humangrowth hormone. J Pharm Sci 87:152–159.


37. Jalalipour M, Gilani K, Tejerzadeh H, NajafabadiAR, Barghi M. 2008. Characterization and aerody-namic evaluation of spray dried recombinanthuman growth hormone using protein stabilizingagents. Int J Pharm 352:209–216.

38. Rathbone MJ, Hadgraft J, Roberts MS. 2002. Mod-ified-release drug delivery technology. New York:Informa Healthcare.

39. Schule S, Shultz-Fademrecht T, Garidel P, Bech-told-Peters K, Friess W. 2008. Stabilization of IgG1in spray-dried powders for inhalation. Eur J PharmBiopharm 69:793–807.

40. Costantino HR, Andya JD, Nguyen PA, Dasovich N,Sweeney TD, Shire SJ, Hsu CC, Maa YF. 1998.Effect of mannitol crystallization on the stabilityand aerosol performance of a spray-dried pharma-ceutical protein, humanized anti-IgE monoclonalantibody. J Pharm Sci 87:1406–1411.

41. Andya JD, Maa YF, Costantino HR, Nguyen PA,Dasovitch N, Sweeney TD, Hsu CC, Shire SJ. 1999.The effect of formulation excipients on proteinstability and aerosol performance of spray-driedpowders of a recombinant humanized anti-IgEmonoclonal antibody 1. Pharm Res 16:350–358.

42. Colonna C, Conti B, Genta I, Alpar OH. 2008. Non-viral dried powders for respiratory gene deliveryprepared by cationic and chitosan loaded liposomes.Int J Pharm 364:108–118.

43. Adi H, Young PM, Cham HK, Stewart P, Agus H,Traini D. 2008. Cospray dried antybiotisc for drypowder lung delivery. J Pharm Sci 97:3356–3366.

44. Darbandi MA, Rouholomini Najafabadi A, Gilani K,Tajerzadeh H. 2008. The effect of vehicles on spraydrying of rifampicin inhalable particles: In vitroand in vivo evaluation. Daru 16:128–135.

45. O’Hara P, Hickey AJ. 2000. Respirable PLGAmicrospheres containing rifampicin for the treat-ment of tuberculosis: Manufacture and character-ization. Pharm Res 17:955–961.

46. Maltesen MJ, Bjerregaard S, Hovgaard L, Have-lund S, van de Weert M. 2008. Quality by design—Spray drying of insulin intended for inhalation. EurJ Pharm Biopharm 70:828–838.

47. Louey MD, Van Oort M, Hickey AJ. 2004. Aerosoldispersion of respirable particles in narrow sizedistributions produced by jet-milling and spray-drying techniques. Pharm Res 21:1200–1206.

48. Corbanie EA, Remon JP, van Reeth K, LandmanWJM, van Eck JHH, Vervaet C. 2007. Spray dryingof an attenuated live Newcastle disease vaccinevirus intended for respiratory mass vaccination ofpoultry. Vaccine 25:8306–8317.

49. Corbanie EA, Vervaet C, van Eck JHH, Remon JP,Landman WJM. 2008. Vaccination of broiler chick-ens with dispersed dry powder vaccines as an alter-native for liquid spray and aerosol vaccination.Vaccine 26:4469–4476.

DOI 10.1002/jps


50. Wong YL, Sampson S, Germishuizen WA, Goone-sekera S, Caponetti G, Sadoff J, Bloom BR,Edwards D. 2007. Drying a tuberculosis vaccinewithout freezing. Proc Natl Acad Sci 104:2591–2595.

51. Amorij JP, Saluja V, Petersen AH, Hinrichs WLJ,Huckriede A, Frijlink HW. 2007. Pulmonary deliv-ery of an insulin-stabilized influenza subunit vac-cine prepared by spray-freeze drying inducessystemic, mucosal humoral as well as cell-mediatedimmune responses in BALB/c mice. Vaccine 25:8707–8717.

52. Ananta E, Volkert M, Knorr D. 2005. Cellularinjuries and storage stability of spray-dried Lacto-bacillus rhamnosus GG. Int Diary J 15:399–409.

53. Luna-Solano G, Salgado-Cervantes MA, Rodriguez-Jimenes GC, Garcia-Alvarado MA. 2005. Optimiza-tion of brewer’s yeast spray dying process. J FoodEng 68:9–18.

54. Kadam KL. 1990. Granulation technology for bio-products. Boston: Informa Healthcare.

55. Palma S, Lujan C, Llabot JM, Barboza G, ManzoRH, Allemandi DA. 2002. Design of Peumus boldus


tablets by direct compression using a novel dryplant extract. Int J Pharm 233:191–198.

56. Prescott JT, Barnum RA. 2000. On powder flow-ability. Pharm Technol 24:60–84.

57. Pereira de Souza T, Martinez-Pacheco R, Gomez-Amoza JL, Petrovick PR. 2007. Eudragit E asexcipient for production of granules and tabletsfrom Phyllantus niruri L spray-dried extract. AAPSPharmSciTech 8:article 34.

58. Soares LAL, Ortega GG, Petrovick PR, Schmidt PC.2005. Optimization of tablets containing high doseof spray-dried plant extract: A technical note. AAPSPharmSciTech 6:article 46.

59. Souza C, Oliveira W. 2006. Powder properties andsystem behavior during spray drying of Bauhiniaforficata Link extract. Drying Technol 24:735–749.

60. Su YL, Fu ZY, Zhang JY, Wang WM, Wang H,Wang YC, Zhang QJ. 2008. Microencapsulation ofRadix salvia miltiorrhiza nanoparticles by spraydrying. Powder Technol 184:114–121.

61. Mujumdar AS. 2006. Handbook of industrial dry-ing. 3rd edition. Boca Raton: CRC Press.


Documents

Spray drying technique: II. Current applications in pharmaceutical technology