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Spray Drying Technique: II. Current Applications in Pharmaceutical Technology
Spray Drying Technique: II. Current Applications in Pharmaceutical 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
ABSTRACT: This review presents current applications of spray drying in pharmaceutical technology. The topics discussed include the obtention of excipients and cospray dried composites, methods for increasing the aqueous solubility and bioavailability of active substances, and modified release profiles from spray-dried particles. This review also 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 the modification of the physical properties of dry plant extracts. ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:587–597, 2010
Keywords: spray drying; cospray drying; spray dryers; aqueous solubility; bioavailability; modified release; inhalation powders; dry plant extracts
INTRODUCTION In pharmaceutical technology, spray drying is typically used as a method for removing water or other liquid from the liquid stream. It is also a very important process used for obtaining dried substances with distinct properties required for various forms of drugs.1–3 The first application of spray drying in a pharmaceutical setting was to obtain dry extracts of active raw materials from plants. Spray drying has become popular in this field due to the ability to dry even the most thermolabile fluid extracts without risking the decomposition of their components. Currently, dry plant extracts are industrially manufactured almost exclusively in this fashion. The spray drying of fluid extracts results in a product with better properties compared to other drying Correspondence to: Krzysztof Cal (Telephone: þ48-58-3493183; Fax: þ48-58-349-3190; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 99, 587–597 (2010) ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association
methods, since spray drying produces homogeneous powders. This review presents and discusses the current, and, we hope, most interesting utilizations in the field of pharmaceutical technology involving the spray drying technique.
EXCIPIENTS AND COSPRAY DRIED COMPOSITES It has been shown that some of the parameters employed in spray drying (mainly inlet temperature and the chamber’s internal moisture content) affect the crystalline structure of certain substances, but other process variables, for example the inlet and liquid feed rates, are also important and inter-related. Lactose is a good example of this phenomenon, because its compressive properties vary after spray drying. Spray-dried lactose was the first substance used to improve the compression properties of other powders.4 The drying process converts dissolved lactose into a mixture that is 55–76% crystalline (depending
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on the drying conditions), and the crystals are conglomerated by an amorphous mass.5 The unique internal structure of the resulting powder yields a material with better plasticity and binding during the process of direct tableting.6 The increased plasticity and binding confer the ability to obtain tablets of increased hardness and lower friability, but their disintegration time does not depend on the compression force used to manufacture the tablets. This kind of lactose is commercially available as Tabletose. The effect of spray drying on mixtures of drug substances and various types of excipients with respect to direct tableting ability has been a subject of extensive studies in recent years. Direct tableting is desirable to drug manufacturers because a powder, which is suitable for direct tableting, does not require further processing (physical or chemical) to create tablets. This is desirable from an economical perspective, but it also improves process performance and facilitates the control of the drug under cGMP requirements. There are several commercially available mixtures that are designed for direct compression, such as Ludipress (a-lactose monohydrate, polyvinyl pyrrolidone, and crospovidon), Cel-O-Cal (cellulose, calcium phosphate), and Microclac 100 (a cospray dried microcrystalline cellulose and lactose monohydrate). These mixtures require only a thorough mixing with the drug substance and other excipients. Solutions or suspensions of active substances and excipients that can be spray-dried and then directly tableted are currently being sought.7 Low molecular mass sugars are difficult to process by spray drying. Frequently, conditions that occur in the spray dryer chamber cause these kinds of excipients to form glassy state deposits on the chamber walls. This results in low yield, extended viscosity of the dried product and its further hygroscopicity. There is no fully effective way to overcome these difficulties. In practice, the highest viscosity of a glassy formation is reached 10–208C above glass transition temperature (Tg). That leads to the conclusion that the temperature of the particle surface should be under that temperature to prevent extensive deposit formation and product loss.8 In general, a temperature of drying that is 108C below Tg seems to be safe; however, Tg for low molecular mass sugars is so low that it is very difficult to maintain a cost effective dried product. The next way to deal with the problem is to add high molecular mass excipients, for example, maltodextrin to raise JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
Tg. It is effective in a predictable way for binary mixtures (sugar–maltodextrin), but for more complex mixtures (sugar–sugar–maltodextrin) it is difficult to predict how high Tg will be. Addition of polymers is not always possible. Intensive studies were performed to develop a single stage cospray dried formulation (dried from one complex feed) for direct compression containing paracetamol and carbohydrates. Despite the above difficulties, the spray drying process gave powders of good flowability and improved tableting ability, which resulted in tablets with good tensile strength,7 and the quantitative optimization of these powders was carried out with use of statistical methods.9 The powders produced showed good rheological properties, and their compression resulted in tablets with satisfactory properties (e.g., friability, disintegration time, and tensile strength). Importantly, studies showed that the quantitative composition of the feed subjected to spray drying had no influence on either the process’s efficiency or the final moisture content in the powder. Based on these findings, formulations containing paracetamol or ibuprofen and adequate amounts of carbohydrates were spray dried on industrial scale. The resulting dry powders were also ready for direct compression.10,11 These studies are of great importance because, by using popular active substances, the authors successfully scaled up the process from a laboratory scale to an industrial scale, which is difficult in spray drying. This demonstrates that the implementation of spray drying to drugs’ manufacture can be very profitable. Also, the use of statistical methods in successfully designing a formulation was validated. It is also possible to change the melting point of an active substance by spray drying, to avoid hot spots (points of spontaneous recrystallization, which appear under the high pressure in the punches) that affect the tablets’ properties. Alginate–lactose coated trandolapril particles prepared by spray drying had a higher melting point and showed no differences in solubility profile relative to the parent crystals.12
INCREASING THE AQUEOUS SOLUBILITY AND BIOAVAILABILITY OF ACTIVE SUBSTANCES The next goal for the technique of cospray drying of active substances with excipients is to increase the drug’s aqueous solubility. This issue is of DOI 10.1002/jps
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importance because about 40% of new active substances have low solubility in water.13,14 Increasing the aqueous solubility of a drug can help in the development of new therapeutic methods. Moreover, approximately half of new drugs cause problems during their formulation process, and fail to became marketed products due to issues related to their high lipophilicity (e.g., low aqueous solubility, low/unrepeatable bioavailability, difficulties in administration).14 The most frequently used method for increasing the aqueous solubility of an active substance is to reduce its particle size, thus increasing the surface area in contact with the solvent.14 While this method is relatively easy to execute and cost-effective, it is not always effective and desirable.15 The simplest way to reduce a substance’s particle size is to micronize the substance, using various types of mills, but this deprives the manufacturer of control over particle properties, such as morphology and surface features. Additionally, grinding in mills can change the crystalline form of the substance, because it is a high-energy process, which can disturb the formulation process and negatively affect the stability of the final drug. Spray drying is another way to produce/create particles with reduced size and to control particle size and morphology if the material is dried from a solution. In addition, it allows for control of the particle’s properties. One example of this is artemisinin, a poorly water-soluble drug that has been spray dried with different ratios of maltodextrin and under different process parameters. The aqueous solubility of the cospray-dried material was related distinctly to process parameters like inlet temperature, concentration in feed, and flow rate, which have the most influence on the particle characteristics responsible for solubility (e.g., particle size and crystallinity rate).16 These relationships can be limiting factors in the reproducibility of the process and its scale up. A study on grizeofulvin provides a particularly valuable example of the use of cospray drying to increase aqueous solubility and bioavailability.17 Grizeofulvin, either alone or with the addition of 0.05% Poloxamer 407, was spray dried from organic solutions using a laboratory dryer. The powders obtained were encapsulated into gelatin capsules and orally administered to rats. The study revealed that the active substance spray dried in combination with a surfactant had better solubility and bioavailability (6.92 mg/mL h 1.98% compared to 3.94 mg/mL h 1.04% for the control DOI 10.1002/jps
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formulation). The solubility of a pure substance after being subjected to spray drying was also higher than the control. However, the pure spraydried substance’s absorption did not change significantly from that of the unmodified substance. Analysis of the particles’ morphology revealed that particle size is not the only factor affecting the solubility and absorption of the substance. The addition of the surfactant resulted in increased particle size, but absorption was improved due to the increased wetability of the particles. The surfactant used was the least toxic among synthetic surfactants and was described as biocompatible (having no adverse effects after oral administration). A similar study was performed on itraconazole. This drug, which has poor water solubility, was subjected to spray drying with surfactants (poloxamer 188, poloxamer 407) in order to achieve a dry powder capable of being redispersed into a stable nanosuspension. Further study also showed improved solubility for itraconazole from a redispersed nanosuspension.18 The simultaneous codrying of a water-insoluble drug (flurbiprofen) with a water-soluble substance (sodium salicylate) is another example of an experiment aimed at increasing the aqueous solubility of active substances. The simultaneous supply of an ethanolic solution and a water solution occurred through a four-fluid nozzle. The composite particles obtained showed higher flurbiprofen release relative to the pure form. The study’s conclusion states that the improved dissolution rate of the flurbiprofen was a surface effect resulting from the rapidly dissolving sodium salicylate.19 The cospray drying of curcumin with PVP gave a solid dispersion with a higher curcumin dissolution rate than a physical mixture of these substances. Spray drying caused the curcumin to convert from a crystalline form into a more soluble amorphous form, and PVP increased the viscosity and disabled the migration of the molecules to constitute a crystalline form.20 Increased bioavailability was also reported for piroxicam, which had been microencapsulated into gelatin shells by spray drying.21 Self-emulsifying drug delivery systems have been the subject of extensive studies recently. These systems are produced by the removal of water from oil-in-water emulsions, followed by the emulsion’s reconstitution via the addition of water ex tempore. During the water removal phase, the matrix substance surrounds the oil phase forming the emulsion, whose size depends on the size of the oily phase’s droplets. This increases these JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
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systems’ stability because they may be stored in the dry form. It also facilitates the use of smaller amounts of surfactant for stabilization purposes. An emulsion containing the anticancer agent 5-PDTT, which has limited aqueous solubility, maltodextrine as a matrix material, sodium caseinate as an emulsifier, and Miglyol 812 as an oily phase, has been the subject of such studies.22 Spray-dried powders of this mixture were subjected to dissolution and bioavailability studies, which revealed a good release and increased bioavailability of the active substance from this drug form. A formulation with nimodipine was also created in a similar way. It was shown that there were no significant differences in bioavailability between the liquid and spray-dried (and redispersed) microemulsions. Both of these microemulsions were characterized by higher bioavailability when compared to traditional tablets.23 Studies on selfemulsifying drug delivery systems demonstrated their ability to remain stable as dry powders and highly redispersible forms, as well as their superiority to conventional drug forms. Selfemulsifying drug delivery systems have their place in further research to increase the aqueous solubility and bioavailability of active substances. Spray drying clearly gives desirable properties like achieving stable dispersions for both emulsion and suspension type formulations. Studies on new formulations are valuable not only in terms of new scientific achievement but also as a method for comparing these formulations with well-established products, and possibly replacing them. Solid-state emulsions prepared by spray drying can also be used as a protective agent for drug substances that are unstable in the gastrointestinal tract.24
MODIFIED RELEASE FROM SPRAY DRIED PARTICLES Spray drying may be a useful tool for the production of modified or delayed release particles. The attempt to produce microcapsules containing vitamin C targeted for release in the colon is an example of such studies.25 Methacrylate polymers, specifically Eudragit RL, RS, and L, were used to coat the active substance. The authors did succeed in generating a release independent of the drug’s concentration but dependent on the polymer’s solubility at a given pH. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
Subjecting a water-in-oil emulsion to spray drying results in a water phase coated by the polymer dissolved in the oily phase. There are well-documented studies in which vancomycin was dissolved in a water phase and in which a copolymer of lactic acid and glycolic acid was dissolved in the outer organic phase, and the emulsion was spray dried.26 This resulted in a rather poor yield (50% of solids) but good particle forming efficiency (up to 99% of the particles incorporated the drug). The particles formed were of an appropriate size for administration into the eye as a suspension (particle size under 11 mm). In vitro and in vivo studies demonstrated the possibility of modifying vancomycin’s release by changing the polymer–vancomycin ratio used in the process. The formulation studied had a greater bioavailability (AUCrel ¼ 2.31) compared to a vancomycin-containing solution. Additionally, no significant effect from hypromelosemediated stabilization on the bioavailability of the vancomycin administered as a suspension was observed. The studied spray-dried emulsion was not stabilized with surfactants. On an industrial scale, this may cause delamination, while the addition of a surfactant may alter the release profile and behavior of the mixture during spray drying. The addition of a biocompatible surfactant might not be strong enough to stabilize this form. Spray drying ketotifen with polymers similar to those mentioned above yielded microsphere delivery systems appropriate for intraperitoneal implantation. Following in vivo implantation, ketotifen release from the microspheres was detected in the plasma after about 350 h.27 The ability to modify an active substance’s release from tablets dry coated with a cospray dried powder containing lactose, sodium alginate, and chitosan has been demonstrated.28 The change in the release rate was dependent on the coating-powder’s method of preparation; and the simple mixing of lactose with a sodium alginate–chitosan complex did not result in an altered release. The cospray-dried powder used for dry coating was characterized by good compression and rheological properties. Tablets coated with this powder had good acid-resistance and a prolonged period of slight release, which was followed by the distinct eruption of the drug substance. The ability to control the delayed release based on the composition of the coating was demonstrated. Thus, it seems possible that spray drying will emerge as a tool for the production of all tablet components. DOI 10.1002/jps
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Due to its unique properties, chitosan is an interesting but sometimes difficult subject of study with respect to controlled release from various types of microparticles, for example, attempts to encapsulate vitamin C by spray drying it with cross-linked chitosan.29 However, these attempts did not result in a significantly delayed release. It is important that microcapsules with good physical properties and stability were produced, which suggests that follow-up studies in this field would be valuable. The use of chitosan as a matrix for paracetamol has also been studied. Microspheres obtained by spray drying have demonstrated markedly delayed release (although not in all concentration ratios). The transformation of paracetamol into its amorphous form and its ability to bind to chitosan via hydrogen bonds has also been demonstrated.30 Similar results were obtained using different equipment for particle preparation, for example, the use of a four fluid nozzle.31 These results show that active ingredient–carrier hydrogen bonding cannot give properly delayed release. Chitosan/ b-cyclodextrin microspheres loaded with theophylline were found to be able to sustain release at low pH, but only 60% of the encapsulated drug was released after 8 h.32
SPRAY DRYING OF PROTEINS Biopharmaceuticals in the solid state are characterized by higher stability than the same substances in solution. Due to this, they may be stored under milder conditions without fear of possible decomposition or disintegration. For a long time, lyophilization has been the most popular method for the production of protein powders. Such products are usually used for parenteral 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 is required, another process must be employed to break-up the lyophilizate. Such a secondary process significantly reduces the efficacy of the whole operation and deprives the operator of control over the properties of the particles generated. As biotechnology has advanced, the need for new methods of protein drying has emerged. Spray drying seems to be the most suitable, mainly due to the protective character of the process of the solvent removal from the material DOI 10.1002/jps
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subjected to drying. Studies have revealed, however, that there are many serious problems related to this method. One of the basic problems lies in the low process efficacy achieved in the most frequently used laboratory spray dryers. In articles where the efficacy is mentioned, it does not exceed 50%.33 This is undesirable not only from an economic point of view but also from the perspective that overall research progress is impeded, since less product means fewer analyses. Laboratory spray dryers are the smallest available and allow for the recovery of only a limited amount of substances from the feed. The processrelated costs and the availability of protein products also remain significant problems. Maury et al.33 have focused on this issue. Their studies were conducted with trehalose, a major carbohydrate used as a carrier in protein formulations intended for spray drying. It was found that the commercial cyclones used in laboratory spray dryers are not able to catch particles smaller than 2 mm, which may have a significant effect on the efficiency of the protein drying process. The authors described a cyclone with different dimensions and demonstrated its superiority. Inappropriate adjustments to the process’s conditions are another potential factor affecting the process efficiency. It is known that process efficiency is heavily dependent on the Tinlet/Toutlet ratio. No significant effect from the nozzle parameters or the drying air flow rate (although the use of the greatest flow rate possible is recommended) has been observed. Prinn et al.34 used statistical analysis to show that, to obtain a balance between yield and particle size, it is necessary to balance the solid content in the liquid stream and the feed rate. Intensive studies have allowed the identification of threats to protein particles during spray drying. Although the risk of thermal denaturation is negligible, proteins often do denature due to dehydration. Thus, it is necessary to supply substances capable of replacing the hydrogen bonding that exists in an aqueous environment (e.g., trehalose). Omitting the protecting substances may lead to disorders in, or the destruction of, a protein’s secondary structure, thus leading to its deactivation. During spray drying, the large particles may be subjected to shearing tension during atomization at the phase (air– water) boundary. Studies have revealed that the process of atomization itself does not produce sufficient tension in particles. Nevertheless, the forces acting upon the droplet-air phase JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
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boundaries during rapid evaporation of solvent are large enough to damage certain sensitive proteins. Recombinant human growth hormone (rhGH) and bovine albumin are examples of such sensitive proteins. The next undesirable process occurs at the phase boundary during the drying process. Particles may undergo aggregation due to shear stress from the air–water interface and produce both soluble and insoluble aggregates. This process can account for some of the denaturation, since aggregation occurs after protein unfolding. It has been shown that adding Zn2þ (associates with protein to form a dimer) and polysorbate 20 can help prevent the formation of soluble and insoluble particle conglomerates, respectively, in the case of rhGH.35,36 Other studies have shown that drying rhGH in the presence of the abovementioned substances results in the formation of particles with properties suitable for subsequent administration via the respiratory tract.37 It is expected that such sets of protecting substances should be effective in aiding other potentially sensitive substances.38 The degree of denaturation on the phase border also depends on the contact area. This is a significant problem due to excessive surface area of the phase boundary (60,000 m2/m3 of 100 mm droplets).1 Maury et al.33 suggest the use of a longer chamber manufactured specifically for this purpose, which will allow for an increase in the droplet size and thus a decrease in the dispersion’s surface area, without losing material on the chamber walls. This is necessary in order to operate on a laboratory scale, as the amount of material at the disposal of an investigator is rarely sufficient for larger dryers, mainly due to the cost of producing the substance. The studies indicate the possibility that the morphology of particles may be manipulated by changing the solid’s concentration in feed, Tinlet, and the content of the protecting substances (low molecular weight sugars are problematic due to their propensity to be involved in glassy state deposits). The difficulties related to the formation of glassy deposits of the amorphous protecting substances on the dryer walls have not yet been completely resolved.
INHALATION POWDERS AND VACCINES Spray drying is often used to produce protein powders designed for administration via the respiratory tract. The resulting particles are of JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
appropriate shape and size to allow for a homogeneous dispersion of aerodynamic properties enabling the particles to reach deep into the bronchial tree. While it is obvious that a powder designed for such a purpose must retain its activity, it is also important that it not change its aerodynamic properties during storage. In the case of an IgG1 antibody formulation spray-dried with mannitol, trehalose, saccharose, and isoleucine and subsequently vacuum dried, it was demonstrated that these substances increase the stability of the stored protein powders and enhance their intrinsic properties.39 However, excipients also have their own properties that can interfere with a drug’s formulation properties. Costantino et al.40 conducted a study on the influence of the crystalline form of mannitol, which is used as a stabilizing agent for an anti-IgE synthetic monoclonal antibody. It was shown that mannitol’s ability to crystallize spontaneously has a great influence on the stability of the dried protein, because it limits stability of protein and aerosolization performance. Continuing this line of exploration, Andya et al.41 performed studies on the influence of other excipients in the process of spray drying to create a stable dry protein powder for pulmonary delivery. Those studies show the complexity of formulating a dry protein powder, not only in terms of avoiding protein degradation, but also in terms of ensuring that the final product is an inhalable powder. Similar investigations into rhGH are discussed above.37 The most recent studies show that it is possible to obtain stable dry powders for gene delivery by spray drying. The spray dried powders had good aerodynamic properties (no agglomeration occurred, cohesive forces between particles had no influence) and stability, while the spray drying process resulted in an acceptable yield of >45%.42 Respiratory antimicrobial agents, especially in combined forms, would be very valuable. Previous studies have shown that spray drying a liquid stream containing doxycycline and ciprofloxacin might produce a dry powder with appropriate aerodynamic properties and greater physical stability than the analogous single spray-dried substance.43 The potential for creating respiratory particles by spray drying has some problems that must be addressed. The morphology of spray-dried particles is very important and depends on many variables. Darbandi et al.44 showed that the ability to create rifampicin particles for inhalation depends on the vehicle in which the spray drying DOI 10.1002/jps
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occurs. O’Hara and Hickey45 showed data on the manufacture and properties of a new form of respiratorily administered rifampicin-loaded PLGA microspheres. They concluded that spray drying is a superior method to manage solvent evaporation and to obtain inhalable microspheres, although in vivo studies are still necessary. Maltesen et al.46 described the process variables influencing spray-dried insulin intended for respiratory delivery. A valuable comparison of two important techniques used in the preparation of inhalable particles, namely, jet milling and spray drying, was presented by Louey et al.47 Both techniques produce very small particles of similar size, but with different morphological properties. Spray drying produced a powder with greater aerosol dispersion. Successful spray drying of protein leads to the possibility of producing vaccines intended for respiratory administration. Vaccines must remain active after drying, physicochemically stable, and ready for aerosolization. It is known that it may be possible to produce active nonviral powders intended for inhalation.42 The formulation and particle engineering aspects of preparing an inhalable dry powder vaccine containing live attenuated Newcastle virus were studied extensively.48 It was shown that the addition of selected stabilizing agents results in the possibility of producing a vaccine suitable for mass vaccination. Further in vivo studies have shown that obtained vaccine is immunologically active.49 Bacterial powders can also be used for the production of immunizing agents. A vaccine for tuberculosis was successfully formulated on a laboratory spray dryer. The vaccine produced sustained 60% of its CFUs and remained relatively stable up to 56 days under accelerated stability test conditions.50 These reports show good prospects for the market implementation of inhalable vaccines. As a modification of the basic spray drying process, spray freezing should also be mentioned. Studies show that the influenza vaccine produced by spray freezing was appropriate for respiratory delivery and gave an even more successful immunization than the traditional intramuscular vaccine.51 It is possible that future studies will show similar prospects for spray-dried powders.
SPRAY DRYING OF VIABLE ORGANISMS Although studies on the drying of microorganisms are usually investigating their utility as a food DOI 10.1002/jps
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source, they are of potential interest as a pharmaceutical technology. The pharmaceutical industry utilizes many viable organisms as ‘‘producers’’ of various biologically active substances or intermediate compounds used to make active substances. Yeasts are utilized mainly as biocatalysts for various chemical reactions, and their availability in powder form facilitates their application and storage and prolongs their viability. In addition, knowledge concerning the behavior of bacteria under spray drying conditions is important, not only due to the possibility that dried mixtures may be contaminated by pathogenic organisms but also due to the gradually increasing significance of probiotic bacteria. Studies have revealed that it is possible to adjust the mixture composition and spray drying conditions in such a way that dry powders or condensed suspensions of microorganisms can be obtained. This is not an easy task, since several mechanisms of bacterial cell damage occur during the spray drying process. These mechanisms are not exclusively due to temperature, and some of them are triggered by the rapid removal of water. What’s more, these mechanisms occur not only at the level of the cellular membrane but also at the level of DNA and ribosomes.52,53 In pharmaceutical manufacturing, the microbiological purity of the resultant products is of the utmost importance. Another advantage of spray drying is that it can be set up as an aseptic process. The use of HEPA filters on the drying and atomizing air, sterilization of the nozzle and chamber walls, and fast product collection ensures the sterility of the product. Since the entire dryer is manufactured from high-quality materials and all wire connections are as short and as straight as possible, sterilization is usually carried out with superheated steam.54 However; aseptic manufacturing via spray drying is a very rare solution due to a lot of specific engineering and high cost, and thus most spray-dried products are sterilized separately when necessary.
MODIFYING THE PROPERTIES OF DRY PLANT EXTRACTS DESIGNED FOR TABLETING OR ENCAPSULATION As mentioned, plant dry extracts are commonly obtained by the spray drying technique. The particles formed by this method are characterized by high hygroscopicity and viscosity, low flowability, and poor suitability for tableting or JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
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encapsulation. Their hygroscopic nature results in lowered stability (either physical or chemical) and the need for special storage conditions. It also affects the powder’s viscosity, which in turn determines its flowability. Nevertheless, the main cause of the powder’s low flowability is the small size of its particles, which is common with spraydried extracts. The small size results in problems related to the powder’s transport on an industrial scale, where uniform mass flow out of bins and other vessels is required. In the case of dry plant extracts, the interactions between the powder particles are often so strong that they do not pour at all. This phenomenon may also generate problems related to obtaining proper mass uniformity in solid dosage forms. In addition, the tablet manufacturing process requires the application of high pressure, which in turn results in tablets that are too hard and give prolonged disintegration times.55 A free-flowing powder is much more important for encapsulation. The mechanism of capsule filling requires the ability to separate small doses of powder from the bulk. The homogeneity of the doses depends on the abovementioned properties to a much greater extent than it does for tablets.56 It is important to differentiate between the rheological properties of the powder and its flowability. The rheological properties depend on the physicochemical properties of the powder and can only change by modification of these physicochemical properties. Flowability, on the other hand, is dependent on the type of surface upon which the pouring of the powder takes place. The smaller the dry extract’s particles, the greater the number of problems related to powder pouring. Therefore, attempts have been made to agglomerate the dry plant extracts in order to improve these properties. The production of agglomerates (wet or dry granulation) is a generally accepted method for improving the flowability and compression properties of dry plant extracts.57,58 The problem with plant extract granulation lies in granules’ heterogeneity. The number of components in the extract makes it difficult to produce identical agglomerates with every repetition; thus, it is difficult to achieve dose uniformity. Furthermore, the stability of many of the active ingredients is unknown. Wet granulation using water is not advisable. Thus, it is difficult to adjust the conditions under which the granulation and the subsequent granulate drying should occur, and it is difficult to select a suitable binding agent. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
To ameliorate these problems, researchers have attempted granulation using Eudragit E in acetone solution. A granulate with a less hygroscopic nature and better rheological properties was obtained.57 An attempt to granulate dry Maytenus ilicifolia extract after the addition of Aerosil as a protecting substance, and either sodium crosscarmelose or microcrystalline cellulose as granulating substances, resulted in similar effects.58 The composition of plant extracts is another cause of difficulties during the spray drying process. Extracts contain many ingredients that demonstrate high viscosity under spray drying conditions (e.g., low molecular-weight sugars and organic acids), which results in an increased tendency to leave undried material deposits on the chamber walls.59 This, in turn, disrupts the chamber’s hydrodynamics and hinders the complete drying of the product. Plant extracts are therefore usually spray dried together with carrier substances intended to facilitate the drying process. Because some of the problems encountered in spray drying plant extracts result from the surface properties of the powder particles, encapsulation by cospray drying might be helpful. Su et al.60 were able to create stable microcapsules from specially prepared nanoparticles of a dry plant extract with good efficiency.
SUMMARY The range of applications presented in this paper does not exhaust the subject of spray drying in pharmaceutical technology. The possibilities are numerous, and they have not yet been fully explored by the pharmaceutical industry. The rapid development of research aimed at extending the application of spray drying, as well as more frequent attempts to incorporate the newest technologies into production, is expected. The literature data suggest that the most popular areas of interest lie in the study of protein drugs, anticancer substances, improvements in the aqueous solubility of active substances, and in many other fields that are very important for modern pharmaceutical technology. Spray drying can successfully replace lyophilization in the manufacturing of parenteral drugs; and the spray-dried products have the advantage of being fine and free-flowing powders, in contrast to lyophilizates. Novel spray-dried forms, such DOI 10.1002/jps
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as nanosuspensions, microemulsions, and microspheres are awaiting utilization in commercial products. Spray-dried self-emulsifying drug delivery systems for oral administration are being developed. The inexpensive, rapidly deployed and easily administered via injection room temperature stable spray dried vaccines, which can be use in the case of global epidemic, are a great challenge and matter of the near future. Spray drying is an energy-intensive process, and the costs of installation and maintenance are also relatively high.61 In addition, the development of broadly adoptable methods is very costintensive. The great problem associated with spray drying, mainly drying of proteins, that must be solved is the transfer and scale up of the process according to the cGMP requirements of the pharmaceutical industry. It will be an expensive and difficult challenge because there are no strict guidelines and examples regarding this process, and often trial and error is the only way to proceed. Nevertheless, the speed and direction of developments in the field of drug administration studies will elucidate the need for the development of spray drying techniques in the pharmaceutical industry.
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compressive powder produced by cospray drying. Drug Dev Ind Pharm 34:248–257. Gonnissen Y, Goncalves SIV, De Geest BG, Remon JP, Vervaet C. 2008. Process design applied to optimize a directly compressible powder via continuous manufacturing process. Eur J Pharm Biopharm 68:760–770. Gonnissen Y, Verhoeven E, Peeters E, Remon JP, Vervaet C. 2008. Coprocessing via spray drying as a formulation platform to improve the compactability of various drugs. Eur J Pharm Biopharm 69:320–334. Makai Z, Bajdik J, Eros I, Pintye-Hodi K. 2008. Evaluation of the effect of lactose on the surface properties of alginate coated trandolapril particles prepared by spray drying. Carbohydrate Polym 74: 712–716. Tang B, Cheng G, Gu JC, Xu CH. 2008. Development of solid self-emulsifying drug delivery systems: Preparation techniques and dosage forms. Drug Discov Today 13:606–612. Gursoy RN, Benita S. 2004. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drug. Biomed Phamacother 58:173– 182. Serajuddin ATM. 1999. Solid dispersion of poorly water-soluble drugs: Early promises, subsequent problems, and recent breakthroughs. J Pharm Sci 88:1058–1066. Sahoo NG, Abbas A, Judeh Z, Li CM, Yuen KH. 2009. Solubility enhancement of a poorly watersoluble anti-malarial drug: Experimental design and use of a modified multifluid nozzle pilot spray drier. J Pharm Sci 98:281–296. Wong SM, Kellaway IW, Murdan S. 2006. Enhancement of the dissolution rate and oral absorption of a poorly water soluble drug by formation of surfactant-containing microparticles. Int J Pharm 317: 61–68. Chaubal MV, Popescu C. 2008. Conversion of nanosuspensions into dry powders by spray drying: A case study. Pharm Res 25:2302–2308. Ozeki T, Beppu S, Mizoe T, Takashima Y, Yuasa H, Okada H. 2006. Preparation of polymeric submicron particle-containing microparticles using 4-fluid spray drier. Pharm Res 23:177–183. Paradkar A, Ambike AA, Jadhav BK, Mahadik KR. 2004. Characterization of curcumin-PVP solid dispersion obtained by spray drying. Int J Pharm 271: 281–286. Piao MG, Yang CW, Li DX, Kim JO, Jang KY, Yoo BK, Kim JA, Woo JS, Lyoo WS, Han SS, Lee YB, Kim DD, Yong CS, Choi HG. 2008. Preparation and in vivo evaluation of piroxicam-loaded gelatin microcapsule by spray drying technique. Biol Pharm Bull 31:1284–1287. Dollo G, Le Corre P, Guerin A, Chevanne F, Burgot JL, Leverge R. 2003. Spray dried oil-in-water emulsion to improve oral bioavailability of poorly soluble drugs. Eur J Pharm Sci 19:273–280.
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23. Yi T, Wan J, Xu H, Yang X. 2008. A new solid selfmicroemulsifying formulation prepared by spray drying of poorly water soluble drugs. Eur J Pharm Biopharm 70:439–444. 24. Ge Z, Zhang XX, Gan L, Gan Y. 2008. Redispersible, dry emulsion of lovastatin protects against intestinal metabolism and improves bioavailability. Acta Pharmacol Sin 29:990–997. 25. Eposito E, Cervellati F, Menegatti E, Nastruzzi C, Cortesi R. 2002. Spray dried Eudragit microparticles as encapsulation devices for vitamin C. Int J Pharm 242:329–334. 26. Gavini E, Chetoni P, Cossu M, Alvarez MG, Saettone MF, Giunchedi P. 2004. PGLA microspheres for the ocular delivery of a peptide drug, vancomycin using emulsification/spray-drying as the preparation method: In vitro/in vivo studies. Eur J Pharm Biopharm 57:207–212. 27. Guerrero S, Muniz E, Teijon C, Olmo R, Teijon JM, Blanco MD. 2008. Ketotifen loaded microspheres prepared by spray-drying poly(D,L-lactide) and poly(D,L-lactide-co-glycolide) polymers: Characterization 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 an ion complex of alginate-chitosan for designing a dry-coated tablet containing a time-controlled releasing function. Pharm Res 17:92–100. 29. Desai KGH, Park HJ. 2005. Encapsulation of vitamin C in triphosphate linked chitosan microspheres by spray drying. J Microencaps 22:179–192. 30. Takahashi H, Chen R, Okamoto H, Danjo K. 2005. Acetaminophen particle design using chitosan and a spray-drying technique. Chem Pharm Bull 53:37– 41. 31. Chen R, Okamoto H, Danjo K. 2006. Particle design using a 4-fluid-nozzle spray-drying technique for sustained release of acetaminophen. Chem Pharm Bull 54:948–953. 32. Zhang WF, Chen XG, Li PW, He QZ, Zhou YH. 2008. Preparation and characterization of theophylline loaded chitosan/b-cyclodextrin microspheres. 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 of spray dried trehalose on a laboratory spray-drier. Eur J Pharm Biopharm 59:565–573. 34. Prinn KB, Costantino HR, Tracy M. 2002. Statistical modeling of protein spray drying at lab scale. AAPS PharmSciTech 3:article 4. 35. Ameri M, Maa YF. 2006. Spray drying of biopharmaceuticals: Stability and process considerations. Drying Technol 24:763–768. 36. Maa YF, Nguyen PA, Whu SW. 2008. Spray-drying of air-liquid interface sensitive recombinant human growth hormone. J Pharm Sci 87:152–159.
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37. Jalalipour M, Gilani K, Tejerzadeh H, Najafabadi AR, Barghi M. 2008. Characterization and aerodynamic evaluation of spray dried recombinant human growth hormone using protein stabilizing agents. Int J Pharm 352:209–216. 38. Rathbone MJ, Hadgraft J, Roberts MS. 2002. Modified-release drug delivery technology. New York: Informa Healthcare. 39. Schule S, Shultz-Fademrecht T, Garidel P, Bechtold-Peters K, Friess W. 2008. Stabilization of IgG1 in spray-dried powders for inhalation. Eur J Pharm Biopharm 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 stability and aerosol performance of a spray-dried pharmaceutical protein, humanized anti-IgE monoclonal antibody. 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 protein stability and aerosol performance of spray-dried powders of a recombinant humanized anti-IgE monoclonal antibody 1. Pharm Res 16:350–358. 42. Colonna C, Conti B, Genta I, Alpar OH. 2008. Nonviral dried powders for respiratory gene delivery prepared 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 dry powder lung delivery. J Pharm Sci 97:3356–3366. 44. Darbandi MA, Rouholomini Najafabadi A, Gilani K, Tajerzadeh H. 2008. The effect of vehicles on spray drying of rifampicin inhalable particles: In vitro and in vivo evaluation. Daru 16:128–135. 45. O’Hara P, Hickey AJ. 2000. Respirable PLGA microspheres containing rifampicin for the treatment of tuberculosis: Manufacture and characterization. Pharm Res 17:955–961. 46. Maltesen MJ, Bjerregaard S, Hovgaard L, Havelund S, van de Weert M. 2008. Quality by design— Spray drying of insulin intended for inhalation. Eur J Pharm Biopharm 70:828–838. 47. Louey MD, Van Oort M, Hickey AJ. 2004. Aerosol dispersion of respirable particles in narrow size distributions produced by jet-milling and spraydrying techniques. Pharm Res 21:1200–1206. 48. Corbanie EA, Remon JP, van Reeth K, Landman WJM, van Eck JHH, Vervaet C. 2007. Spray drying of an attenuated live Newcastle disease vaccine virus intended for respiratory mass vaccination of poultry. Vaccine 25:8306–8317. 49. Corbanie EA, Vervaet C, van Eck JHH, Remon JP, Landman WJM. 2008. Vaccination of broiler chickens with dispersed dry powder vaccines as an alternative for liquid spray and aerosol vaccination. Vaccine 26:4469–4476.
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50. Wong YL, Sampson S, Germishuizen WA, Goonesekera S, Caponetti G, Sadoff J, Bloom BR, Edwards D. 2007. Drying a tuberculosis vaccine without freezing. Proc Natl Acad Sci 104:2591– 2595. 51. Amorij JP, Saluja V, Petersen AH, Hinrichs WLJ, Huckriede A, Frijlink HW. 2007. Pulmonary delivery of an insulin-stabilized influenza subunit vaccine prepared by spray-freeze drying induces systemic, mucosal humoral as well as cell-mediated immune responses in BALB/c mice. Vaccine 25: 8707–8717. 52. Ananta E, Volkert M, Knorr D. 2005. Cellular injuries and storage stability of spray-dried Lactobacillus rhamnosus GG. Int Diary J 15:399–409. 53. Luna-Solano G, Salgado-Cervantes MA, RodriguezJimenes GC, Garcia-Alvarado MA. 2005. Optimization of brewer’s yeast spray dying process. J Food Eng 68:9–18. 54. Kadam KL. 1990. Granulation technology for bioproducts. Boston: Informa Healthcare. 55. Palma S, Lujan C, Llabot JM, Barboza G, Manzo RH, Allemandi DA. 2002. Design of Peumus boldus
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tablets by direct compression using a novel dry plant extract. Int J Pharm 233:191–198. Prescott JT, Barnum RA. 2000. On powder flowability. Pharm Technol 24:60–84. Pereira de Souza T, Martinez-Pacheco R, GomezAmoza JL, Petrovick PR. 2007. Eudragit E as excipient for production of granules and tablets from Phyllantus niruri L spray-dried extract. AAPS PharmSciTech 8:article 34. Soares LAL, Ortega GG, Petrovick PR, Schmidt PC. 2005. Optimization of tablets containing high dose of spray-dried plant extract: A technical note. AAPS PharmSciTech 6:article 46. Souza C, Oliveira W. 2006. Powder properties and system behavior during spray drying of Bauhinia forficata Link extract. Drying Technol 24:735– 749. Su YL, Fu ZY, Zhang JY, Wang WM, Wang H, Wang YC, Zhang QJ. 2008. Microencapsulation of Radix salvia miltiorrhiza nanoparticles by spray drying. Powder Technol 184:114–121. Mujumdar AS. 2006. Handbook of industrial drying. 3rd edition. Boca Raton: CRC Press.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
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
ABSTRACT: This review presents current applications of spray drying in pharmaceutical technology. The topics discussed include the obtention of excipients and cospray dried composites, methods for increasing the aqueous solubility and bioavailability of active substances, and modified release profiles from spray-dried particles. This review also 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 the modification of the physical properties of dry plant extracts. ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:587–597, 2010
Keywords: spray drying; cospray drying; spray dryers; aqueous solubility; bioavailability; modified release; inhalation powders; dry plant extracts
INTRODUCTION In pharmaceutical technology, spray drying is typically used as a method for removing water or other liquid from the liquid stream. It is also a very important process used for obtaining dried substances with distinct properties required for various forms of drugs.1–3 The first application of spray drying in a pharmaceutical setting was to obtain dry extracts of active raw materials from plants. Spray drying has become popular in this field due to the ability to dry even the most thermolabile fluid extracts without risking the decomposition of their components. Currently, dry plant extracts are industrially manufactured almost exclusively in this fashion. The spray drying of fluid extracts results in a product with better properties compared to other drying Correspondence to: Krzysztof Cal (Telephone: þ48-58-3493183; Fax: þ48-58-349-3190; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 99, 587–597 (2010) ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association
methods, since spray drying produces homogeneous powders. This review presents and discusses the current, and, we hope, most interesting utilizations in the field of pharmaceutical technology involving the spray drying technique.
EXCIPIENTS AND COSPRAY DRIED COMPOSITES It has been shown that some of the parameters employed in spray drying (mainly inlet temperature and the chamber’s internal moisture content) affect the crystalline structure of certain substances, but other process variables, for example the inlet and liquid feed rates, are also important and inter-related. Lactose is a good example of this phenomenon, because its compressive properties vary after spray drying. Spray-dried lactose was the first substance used to improve the compression properties of other powders.4 The drying process converts dissolved lactose into a mixture that is 55–76% crystalline (depending
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on the drying conditions), and the crystals are conglomerated by an amorphous mass.5 The unique internal structure of the resulting powder yields a material with better plasticity and binding during the process of direct tableting.6 The increased plasticity and binding confer the ability to obtain tablets of increased hardness and lower friability, but their disintegration time does not depend on the compression force used to manufacture the tablets. This kind of lactose is commercially available as Tabletose. The effect of spray drying on mixtures of drug substances and various types of excipients with respect to direct tableting ability has been a subject of extensive studies in recent years. Direct tableting is desirable to drug manufacturers because a powder, which is suitable for direct tableting, does not require further processing (physical or chemical) to create tablets. This is desirable from an economical perspective, but it also improves process performance and facilitates the control of the drug under cGMP requirements. There are several commercially available mixtures that are designed for direct compression, such as Ludipress (a-lactose monohydrate, polyvinyl pyrrolidone, and crospovidon), Cel-O-Cal (cellulose, calcium phosphate), and Microclac 100 (a cospray dried microcrystalline cellulose and lactose monohydrate). These mixtures require only a thorough mixing with the drug substance and other excipients. Solutions or suspensions of active substances and excipients that can be spray-dried and then directly tableted are currently being sought.7 Low molecular mass sugars are difficult to process by spray drying. Frequently, conditions that occur in the spray dryer chamber cause these kinds of excipients to form glassy state deposits on the chamber walls. This results in low yield, extended viscosity of the dried product and its further hygroscopicity. There is no fully effective way to overcome these difficulties. In practice, the highest viscosity of a glassy formation is reached 10–208C above glass transition temperature (Tg). That leads to the conclusion that the temperature of the particle surface should be under that temperature to prevent extensive deposit formation and product loss.8 In general, a temperature of drying that is 108C below Tg seems to be safe; however, Tg for low molecular mass sugars is so low that it is very difficult to maintain a cost effective dried product. The next way to deal with the problem is to add high molecular mass excipients, for example, maltodextrin to raise JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
Tg. It is effective in a predictable way for binary mixtures (sugar–maltodextrin), but for more complex mixtures (sugar–sugar–maltodextrin) it is difficult to predict how high Tg will be. Addition of polymers is not always possible. Intensive studies were performed to develop a single stage cospray dried formulation (dried from one complex feed) for direct compression containing paracetamol and carbohydrates. Despite the above difficulties, the spray drying process gave powders of good flowability and improved tableting ability, which resulted in tablets with good tensile strength,7 and the quantitative optimization of these powders was carried out with use of statistical methods.9 The powders produced showed good rheological properties, and their compression resulted in tablets with satisfactory properties (e.g., friability, disintegration time, and tensile strength). Importantly, studies showed that the quantitative composition of the feed subjected to spray drying had no influence on either the process’s efficiency or the final moisture content in the powder. Based on these findings, formulations containing paracetamol or ibuprofen and adequate amounts of carbohydrates were spray dried on industrial scale. The resulting dry powders were also ready for direct compression.10,11 These studies are of great importance because, by using popular active substances, the authors successfully scaled up the process from a laboratory scale to an industrial scale, which is difficult in spray drying. This demonstrates that the implementation of spray drying to drugs’ manufacture can be very profitable. Also, the use of statistical methods in successfully designing a formulation was validated. It is also possible to change the melting point of an active substance by spray drying, to avoid hot spots (points of spontaneous recrystallization, which appear under the high pressure in the punches) that affect the tablets’ properties. Alginate–lactose coated trandolapril particles prepared by spray drying had a higher melting point and showed no differences in solubility profile relative to the parent crystals.12
INCREASING THE AQUEOUS SOLUBILITY AND BIOAVAILABILITY OF ACTIVE SUBSTANCES The next goal for the technique of cospray drying of active substances with excipients is to increase the drug’s aqueous solubility. This issue is of DOI 10.1002/jps
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importance because about 40% of new active substances have low solubility in water.13,14 Increasing the aqueous solubility of a drug can help in the development of new therapeutic methods. Moreover, approximately half of new drugs cause problems during their formulation process, and fail to became marketed products due to issues related to their high lipophilicity (e.g., low aqueous solubility, low/unrepeatable bioavailability, difficulties in administration).14 The most frequently used method for increasing the aqueous solubility of an active substance is to reduce its particle size, thus increasing the surface area in contact with the solvent.14 While this method is relatively easy to execute and cost-effective, it is not always effective and desirable.15 The simplest way to reduce a substance’s particle size is to micronize the substance, using various types of mills, but this deprives the manufacturer of control over particle properties, such as morphology and surface features. Additionally, grinding in mills can change the crystalline form of the substance, because it is a high-energy process, which can disturb the formulation process and negatively affect the stability of the final drug. Spray drying is another way to produce/create particles with reduced size and to control particle size and morphology if the material is dried from a solution. In addition, it allows for control of the particle’s properties. One example of this is artemisinin, a poorly water-soluble drug that has been spray dried with different ratios of maltodextrin and under different process parameters. The aqueous solubility of the cospray-dried material was related distinctly to process parameters like inlet temperature, concentration in feed, and flow rate, which have the most influence on the particle characteristics responsible for solubility (e.g., particle size and crystallinity rate).16 These relationships can be limiting factors in the reproducibility of the process and its scale up. A study on grizeofulvin provides a particularly valuable example of the use of cospray drying to increase aqueous solubility and bioavailability.17 Grizeofulvin, either alone or with the addition of 0.05% Poloxamer 407, was spray dried from organic solutions using a laboratory dryer. The powders obtained were encapsulated into gelatin capsules and orally administered to rats. The study revealed that the active substance spray dried in combination with a surfactant had better solubility and bioavailability (6.92 mg/mL h 1.98% compared to 3.94 mg/mL h 1.04% for the control DOI 10.1002/jps
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formulation). The solubility of a pure substance after being subjected to spray drying was also higher than the control. However, the pure spraydried substance’s absorption did not change significantly from that of the unmodified substance. Analysis of the particles’ morphology revealed that particle size is not the only factor affecting the solubility and absorption of the substance. The addition of the surfactant resulted in increased particle size, but absorption was improved due to the increased wetability of the particles. The surfactant used was the least toxic among synthetic surfactants and was described as biocompatible (having no adverse effects after oral administration). A similar study was performed on itraconazole. This drug, which has poor water solubility, was subjected to spray drying with surfactants (poloxamer 188, poloxamer 407) in order to achieve a dry powder capable of being redispersed into a stable nanosuspension. Further study also showed improved solubility for itraconazole from a redispersed nanosuspension.18 The simultaneous codrying of a water-insoluble drug (flurbiprofen) with a water-soluble substance (sodium salicylate) is another example of an experiment aimed at increasing the aqueous solubility of active substances. The simultaneous supply of an ethanolic solution and a water solution occurred through a four-fluid nozzle. The composite particles obtained showed higher flurbiprofen release relative to the pure form. The study’s conclusion states that the improved dissolution rate of the flurbiprofen was a surface effect resulting from the rapidly dissolving sodium salicylate.19 The cospray drying of curcumin with PVP gave a solid dispersion with a higher curcumin dissolution rate than a physical mixture of these substances. Spray drying caused the curcumin to convert from a crystalline form into a more soluble amorphous form, and PVP increased the viscosity and disabled the migration of the molecules to constitute a crystalline form.20 Increased bioavailability was also reported for piroxicam, which had been microencapsulated into gelatin shells by spray drying.21 Self-emulsifying drug delivery systems have been the subject of extensive studies recently. These systems are produced by the removal of water from oil-in-water emulsions, followed by the emulsion’s reconstitution via the addition of water ex tempore. During the water removal phase, the matrix substance surrounds the oil phase forming the emulsion, whose size depends on the size of the oily phase’s droplets. This increases these JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
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systems’ stability because they may be stored in the dry form. It also facilitates the use of smaller amounts of surfactant for stabilization purposes. An emulsion containing the anticancer agent 5-PDTT, which has limited aqueous solubility, maltodextrine as a matrix material, sodium caseinate as an emulsifier, and Miglyol 812 as an oily phase, has been the subject of such studies.22 Spray-dried powders of this mixture were subjected to dissolution and bioavailability studies, which revealed a good release and increased bioavailability of the active substance from this drug form. A formulation with nimodipine was also created in a similar way. It was shown that there were no significant differences in bioavailability between the liquid and spray-dried (and redispersed) microemulsions. Both of these microemulsions were characterized by higher bioavailability when compared to traditional tablets.23 Studies on selfemulsifying drug delivery systems demonstrated their ability to remain stable as dry powders and highly redispersible forms, as well as their superiority to conventional drug forms. Selfemulsifying drug delivery systems have their place in further research to increase the aqueous solubility and bioavailability of active substances. Spray drying clearly gives desirable properties like achieving stable dispersions for both emulsion and suspension type formulations. Studies on new formulations are valuable not only in terms of new scientific achievement but also as a method for comparing these formulations with well-established products, and possibly replacing them. Solid-state emulsions prepared by spray drying can also be used as a protective agent for drug substances that are unstable in the gastrointestinal tract.24
MODIFIED RELEASE FROM SPRAY DRIED PARTICLES Spray drying may be a useful tool for the production of modified or delayed release particles. The attempt to produce microcapsules containing vitamin C targeted for release in the colon is an example of such studies.25 Methacrylate polymers, specifically Eudragit RL, RS, and L, were used to coat the active substance. The authors did succeed in generating a release independent of the drug’s concentration but dependent on the polymer’s solubility at a given pH. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
Subjecting a water-in-oil emulsion to spray drying results in a water phase coated by the polymer dissolved in the oily phase. There are well-documented studies in which vancomycin was dissolved in a water phase and in which a copolymer of lactic acid and glycolic acid was dissolved in the outer organic phase, and the emulsion was spray dried.26 This resulted in a rather poor yield (50% of solids) but good particle forming efficiency (up to 99% of the particles incorporated the drug). The particles formed were of an appropriate size for administration into the eye as a suspension (particle size under 11 mm). In vitro and in vivo studies demonstrated the possibility of modifying vancomycin’s release by changing the polymer–vancomycin ratio used in the process. The formulation studied had a greater bioavailability (AUCrel ¼ 2.31) compared to a vancomycin-containing solution. Additionally, no significant effect from hypromelosemediated stabilization on the bioavailability of the vancomycin administered as a suspension was observed. The studied spray-dried emulsion was not stabilized with surfactants. On an industrial scale, this may cause delamination, while the addition of a surfactant may alter the release profile and behavior of the mixture during spray drying. The addition of a biocompatible surfactant might not be strong enough to stabilize this form. Spray drying ketotifen with polymers similar to those mentioned above yielded microsphere delivery systems appropriate for intraperitoneal implantation. Following in vivo implantation, ketotifen release from the microspheres was detected in the plasma after about 350 h.27 The ability to modify an active substance’s release from tablets dry coated with a cospray dried powder containing lactose, sodium alginate, and chitosan has been demonstrated.28 The change in the release rate was dependent on the coating-powder’s method of preparation; and the simple mixing of lactose with a sodium alginate–chitosan complex did not result in an altered release. The cospray-dried powder used for dry coating was characterized by good compression and rheological properties. Tablets coated with this powder had good acid-resistance and a prolonged period of slight release, which was followed by the distinct eruption of the drug substance. The ability to control the delayed release based on the composition of the coating was demonstrated. Thus, it seems possible that spray drying will emerge as a tool for the production of all tablet components. DOI 10.1002/jps
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Due to its unique properties, chitosan is an interesting but sometimes difficult subject of study with respect to controlled release from various types of microparticles, for example, attempts to encapsulate vitamin C by spray drying it with cross-linked chitosan.29 However, these attempts did not result in a significantly delayed release. It is important that microcapsules with good physical properties and stability were produced, which suggests that follow-up studies in this field would be valuable. The use of chitosan as a matrix for paracetamol has also been studied. Microspheres obtained by spray drying have demonstrated markedly delayed release (although not in all concentration ratios). The transformation of paracetamol into its amorphous form and its ability to bind to chitosan via hydrogen bonds has also been demonstrated.30 Similar results were obtained using different equipment for particle preparation, for example, the use of a four fluid nozzle.31 These results show that active ingredient–carrier hydrogen bonding cannot give properly delayed release. Chitosan/ b-cyclodextrin microspheres loaded with theophylline were found to be able to sustain release at low pH, but only 60% of the encapsulated drug was released after 8 h.32
SPRAY DRYING OF PROTEINS Biopharmaceuticals in the solid state are characterized by higher stability than the same substances in solution. Due to this, they may be stored under milder conditions without fear of possible decomposition or disintegration. For a long time, lyophilization has been the most popular method for the production of protein powders. Such products are usually used for parenteral 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 is required, another process must be employed to break-up the lyophilizate. Such a secondary process significantly reduces the efficacy of the whole operation and deprives the operator of control over the properties of the particles generated. As biotechnology has advanced, the need for new methods of protein drying has emerged. Spray drying seems to be the most suitable, mainly due to the protective character of the process of the solvent removal from the material DOI 10.1002/jps
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subjected to drying. Studies have revealed, however, that there are many serious problems related to this method. One of the basic problems lies in the low process efficacy achieved in the most frequently used laboratory spray dryers. In articles where the efficacy is mentioned, it does not exceed 50%.33 This is undesirable not only from an economic point of view but also from the perspective that overall research progress is impeded, since less product means fewer analyses. Laboratory spray dryers are the smallest available and allow for the recovery of only a limited amount of substances from the feed. The processrelated costs and the availability of protein products also remain significant problems. Maury et al.33 have focused on this issue. Their studies were conducted with trehalose, a major carbohydrate used as a carrier in protein formulations intended for spray drying. It was found that the commercial cyclones used in laboratory spray dryers are not able to catch particles smaller than 2 mm, which may have a significant effect on the efficiency of the protein drying process. The authors described a cyclone with different dimensions and demonstrated its superiority. Inappropriate adjustments to the process’s conditions are another potential factor affecting the process efficiency. It is known that process efficiency is heavily dependent on the Tinlet/Toutlet ratio. No significant effect from the nozzle parameters or the drying air flow rate (although the use of the greatest flow rate possible is recommended) has been observed. Prinn et al.34 used statistical analysis to show that, to obtain a balance between yield and particle size, it is necessary to balance the solid content in the liquid stream and the feed rate. Intensive studies have allowed the identification of threats to protein particles during spray drying. Although the risk of thermal denaturation is negligible, proteins often do denature due to dehydration. Thus, it is necessary to supply substances capable of replacing the hydrogen bonding that exists in an aqueous environment (e.g., trehalose). Omitting the protecting substances may lead to disorders in, or the destruction of, a protein’s secondary structure, thus leading to its deactivation. During spray drying, the large particles may be subjected to shearing tension during atomization at the phase (air– water) boundary. Studies have revealed that the process of atomization itself does not produce sufficient tension in particles. Nevertheless, the forces acting upon the droplet-air phase JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
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boundaries during rapid evaporation of solvent are large enough to damage certain sensitive proteins. Recombinant human growth hormone (rhGH) and bovine albumin are examples of such sensitive proteins. The next undesirable process occurs at the phase boundary during the drying process. Particles may undergo aggregation due to shear stress from the air–water interface and produce both soluble and insoluble aggregates. This process can account for some of the denaturation, since aggregation occurs after protein unfolding. It has been shown that adding Zn2þ (associates with protein to form a dimer) and polysorbate 20 can help prevent the formation of soluble and insoluble particle conglomerates, respectively, in the case of rhGH.35,36 Other studies have shown that drying rhGH in the presence of the abovementioned substances results in the formation of particles with properties suitable for subsequent administration via the respiratory tract.37 It is expected that such sets of protecting substances should be effective in aiding other potentially sensitive substances.38 The degree of denaturation on the phase border also depends on the contact area. This is a significant problem due to excessive surface area of the phase boundary (60,000 m2/m3 of 100 mm droplets).1 Maury et al.33 suggest the use of a longer chamber manufactured specifically for this purpose, which will allow for an increase in the droplet size and thus a decrease in the dispersion’s surface area, without losing material on the chamber walls. This is necessary in order to operate on a laboratory scale, as the amount of material at the disposal of an investigator is rarely sufficient for larger dryers, mainly due to the cost of producing the substance. The studies indicate the possibility that the morphology of particles may be manipulated by changing the solid’s concentration in feed, Tinlet, and the content of the protecting substances (low molecular weight sugars are problematic due to their propensity to be involved in glassy state deposits). The difficulties related to the formation of glassy deposits of the amorphous protecting substances on the dryer walls have not yet been completely resolved.
INHALATION POWDERS AND VACCINES Spray drying is often used to produce protein powders designed for administration via the respiratory tract. The resulting particles are of JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
appropriate shape and size to allow for a homogeneous dispersion of aerodynamic properties enabling the particles to reach deep into the bronchial tree. While it is obvious that a powder designed for such a purpose must retain its activity, it is also important that it not change its aerodynamic properties during storage. In the case of an IgG1 antibody formulation spray-dried with mannitol, trehalose, saccharose, and isoleucine and subsequently vacuum dried, it was demonstrated that these substances increase the stability of the stored protein powders and enhance their intrinsic properties.39 However, excipients also have their own properties that can interfere with a drug’s formulation properties. Costantino et al.40 conducted a study on the influence of the crystalline form of mannitol, which is used as a stabilizing agent for an anti-IgE synthetic monoclonal antibody. It was shown that mannitol’s ability to crystallize spontaneously has a great influence on the stability of the dried protein, because it limits stability of protein and aerosolization performance. Continuing this line of exploration, Andya et al.41 performed studies on the influence of other excipients in the process of spray drying to create a stable dry protein powder for pulmonary delivery. Those studies show the complexity of formulating a dry protein powder, not only in terms of avoiding protein degradation, but also in terms of ensuring that the final product is an inhalable powder. Similar investigations into rhGH are discussed above.37 The most recent studies show that it is possible to obtain stable dry powders for gene delivery by spray drying. The spray dried powders had good aerodynamic properties (no agglomeration occurred, cohesive forces between particles had no influence) and stability, while the spray drying process resulted in an acceptable yield of >45%.42 Respiratory antimicrobial agents, especially in combined forms, would be very valuable. Previous studies have shown that spray drying a liquid stream containing doxycycline and ciprofloxacin might produce a dry powder with appropriate aerodynamic properties and greater physical stability than the analogous single spray-dried substance.43 The potential for creating respiratory particles by spray drying has some problems that must be addressed. The morphology of spray-dried particles is very important and depends on many variables. Darbandi et al.44 showed that the ability to create rifampicin particles for inhalation depends on the vehicle in which the spray drying DOI 10.1002/jps
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occurs. O’Hara and Hickey45 showed data on the manufacture and properties of a new form of respiratorily administered rifampicin-loaded PLGA microspheres. They concluded that spray drying is a superior method to manage solvent evaporation and to obtain inhalable microspheres, although in vivo studies are still necessary. Maltesen et al.46 described the process variables influencing spray-dried insulin intended for respiratory delivery. A valuable comparison of two important techniques used in the preparation of inhalable particles, namely, jet milling and spray drying, was presented by Louey et al.47 Both techniques produce very small particles of similar size, but with different morphological properties. Spray drying produced a powder with greater aerosol dispersion. Successful spray drying of protein leads to the possibility of producing vaccines intended for respiratory administration. Vaccines must remain active after drying, physicochemically stable, and ready for aerosolization. It is known that it may be possible to produce active nonviral powders intended for inhalation.42 The formulation and particle engineering aspects of preparing an inhalable dry powder vaccine containing live attenuated Newcastle virus were studied extensively.48 It was shown that the addition of selected stabilizing agents results in the possibility of producing a vaccine suitable for mass vaccination. Further in vivo studies have shown that obtained vaccine is immunologically active.49 Bacterial powders can also be used for the production of immunizing agents. A vaccine for tuberculosis was successfully formulated on a laboratory spray dryer. The vaccine produced sustained 60% of its CFUs and remained relatively stable up to 56 days under accelerated stability test conditions.50 These reports show good prospects for the market implementation of inhalable vaccines. As a modification of the basic spray drying process, spray freezing should also be mentioned. Studies show that the influenza vaccine produced by spray freezing was appropriate for respiratory delivery and gave an even more successful immunization than the traditional intramuscular vaccine.51 It is possible that future studies will show similar prospects for spray-dried powders.
SPRAY DRYING OF VIABLE ORGANISMS Although studies on the drying of microorganisms are usually investigating their utility as a food DOI 10.1002/jps
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source, they are of potential interest as a pharmaceutical technology. The pharmaceutical industry utilizes many viable organisms as ‘‘producers’’ of various biologically active substances or intermediate compounds used to make active substances. Yeasts are utilized mainly as biocatalysts for various chemical reactions, and their availability in powder form facilitates their application and storage and prolongs their viability. In addition, knowledge concerning the behavior of bacteria under spray drying conditions is important, not only due to the possibility that dried mixtures may be contaminated by pathogenic organisms but also due to the gradually increasing significance of probiotic bacteria. Studies have revealed that it is possible to adjust the mixture composition and spray drying conditions in such a way that dry powders or condensed suspensions of microorganisms can be obtained. This is not an easy task, since several mechanisms of bacterial cell damage occur during the spray drying process. These mechanisms are not exclusively due to temperature, and some of them are triggered by the rapid removal of water. What’s more, these mechanisms occur not only at the level of the cellular membrane but also at the level of DNA and ribosomes.52,53 In pharmaceutical manufacturing, the microbiological purity of the resultant products is of the utmost importance. Another advantage of spray drying is that it can be set up as an aseptic process. The use of HEPA filters on the drying and atomizing air, sterilization of the nozzle and chamber walls, and fast product collection ensures the sterility of the product. Since the entire dryer is manufactured from high-quality materials and all wire connections are as short and as straight as possible, sterilization is usually carried out with superheated steam.54 However; aseptic manufacturing via spray drying is a very rare solution due to a lot of specific engineering and high cost, and thus most spray-dried products are sterilized separately when necessary.
MODIFYING THE PROPERTIES OF DRY PLANT EXTRACTS DESIGNED FOR TABLETING OR ENCAPSULATION As mentioned, plant dry extracts are commonly obtained by the spray drying technique. The particles formed by this method are characterized by high hygroscopicity and viscosity, low flowability, and poor suitability for tableting or JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
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encapsulation. Their hygroscopic nature results in lowered stability (either physical or chemical) and the need for special storage conditions. It also affects the powder’s viscosity, which in turn determines its flowability. Nevertheless, the main cause of the powder’s low flowability is the small size of its particles, which is common with spraydried extracts. The small size results in problems related to the powder’s transport on an industrial scale, where uniform mass flow out of bins and other vessels is required. In the case of dry plant extracts, the interactions between the powder particles are often so strong that they do not pour at all. This phenomenon may also generate problems related to obtaining proper mass uniformity in solid dosage forms. In addition, the tablet manufacturing process requires the application of high pressure, which in turn results in tablets that are too hard and give prolonged disintegration times.55 A free-flowing powder is much more important for encapsulation. The mechanism of capsule filling requires the ability to separate small doses of powder from the bulk. The homogeneity of the doses depends on the abovementioned properties to a much greater extent than it does for tablets.56 It is important to differentiate between the rheological properties of the powder and its flowability. The rheological properties depend on the physicochemical properties of the powder and can only change by modification of these physicochemical properties. Flowability, on the other hand, is dependent on the type of surface upon which the pouring of the powder takes place. The smaller the dry extract’s particles, the greater the number of problems related to powder pouring. Therefore, attempts have been made to agglomerate the dry plant extracts in order to improve these properties. The production of agglomerates (wet or dry granulation) is a generally accepted method for improving the flowability and compression properties of dry plant extracts.57,58 The problem with plant extract granulation lies in granules’ heterogeneity. The number of components in the extract makes it difficult to produce identical agglomerates with every repetition; thus, it is difficult to achieve dose uniformity. Furthermore, the stability of many of the active ingredients is unknown. Wet granulation using water is not advisable. Thus, it is difficult to adjust the conditions under which the granulation and the subsequent granulate drying should occur, and it is difficult to select a suitable binding agent. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
To ameliorate these problems, researchers have attempted granulation using Eudragit E in acetone solution. A granulate with a less hygroscopic nature and better rheological properties was obtained.57 An attempt to granulate dry Maytenus ilicifolia extract after the addition of Aerosil as a protecting substance, and either sodium crosscarmelose or microcrystalline cellulose as granulating substances, resulted in similar effects.58 The composition of plant extracts is another cause of difficulties during the spray drying process. Extracts contain many ingredients that demonstrate high viscosity under spray drying conditions (e.g., low molecular-weight sugars and organic acids), which results in an increased tendency to leave undried material deposits on the chamber walls.59 This, in turn, disrupts the chamber’s hydrodynamics and hinders the complete drying of the product. Plant extracts are therefore usually spray dried together with carrier substances intended to facilitate the drying process. Because some of the problems encountered in spray drying plant extracts result from the surface properties of the powder particles, encapsulation by cospray drying might be helpful. Su et al.60 were able to create stable microcapsules from specially prepared nanoparticles of a dry plant extract with good efficiency.
SUMMARY The range of applications presented in this paper does not exhaust the subject of spray drying in pharmaceutical technology. The possibilities are numerous, and they have not yet been fully explored by the pharmaceutical industry. The rapid development of research aimed at extending the application of spray drying, as well as more frequent attempts to incorporate the newest technologies into production, is expected. The literature data suggest that the most popular areas of interest lie in the study of protein drugs, anticancer substances, improvements in the aqueous solubility of active substances, and in many other fields that are very important for modern pharmaceutical technology. Spray drying can successfully replace lyophilization in the manufacturing of parenteral drugs; and the spray-dried products have the advantage of being fine and free-flowing powders, in contrast to lyophilizates. Novel spray-dried forms, such DOI 10.1002/jps
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as nanosuspensions, microemulsions, and microspheres are awaiting utilization in commercial products. Spray-dried self-emulsifying drug delivery systems for oral administration are being developed. The inexpensive, rapidly deployed and easily administered via injection room temperature stable spray dried vaccines, which can be use in the case of global epidemic, are a great challenge and matter of the near future. Spray drying is an energy-intensive process, and the costs of installation and maintenance are also relatively high.61 In addition, the development of broadly adoptable methods is very costintensive. The great problem associated with spray drying, mainly drying of proteins, that must be solved is the transfer and scale up of the process according to the cGMP requirements of the pharmaceutical industry. It will be an expensive and difficult challenge because there are no strict guidelines and examples regarding this process, and often trial and error is the only way to proceed. Nevertheless, the speed and direction of developments in the field of drug administration studies will elucidate the need for the development of spray drying techniques in the pharmaceutical industry.
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