Improved Dissolution of an Insoluble Drug Using a 4-Fluid Nozzle Spray-Drying Technique

Chen, Richer; Tagawa, Maya; Hoshi, N.; Ogura, Tsugio; Okamoto, Hirokazu; Danjo, Kazumi

doi:10.1248/cpb.52.1066

Cited by 28 publications

(15 citation statements)

References 29 publications

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“…Excipients, which have been commonly recognized as stabilizing agents for amorphous materials, include the hydrophilic organic polymers: polyvinylpyrrolidone (5,6), various cellulose derivatives e.g. hydroxypropylcellulose (6), and hydroxypropylmethylcellulose (7). The proposed mechanism for the stabilizing effect of these polymers is an increase in glass transition temperature of the binary mixture and in some cases specific drug polymer interactions (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Scaling Up the Spray Drying Process from Pilot to Production Scale Using an Atomized Droplet Size Criterion

Thybo

Hovgaard

Lindeløv³

et al. 2008

Pharm Res

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Section: Introductionmentioning

confidence: 99%

Scaling Up the Spray Drying Process from Pilot to Production Scale Using an Atomized Droplet Size Criterion

Thybo

Hovgaard

Lindeløv³

et al. 2008

Pharm Res

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“…3,4) Improving the dissolution rate of these compounds is achieved through various approaches of formulation technology. These include particle size reduction/ milling, [5][6][7][8] solution-based precipitation, solid dispersion by hot melt extrusion 9) or spray-drying, 10,11) complexation with cyclodextrins 12,13) and so on, as also described extensively in reviews. 14,15) Cryogenic technologies such as freeze drying 16) and spray freezing into liquid (SFL), [17][18][19] in particular, have lately attracted considerable attention for BCS class II compounds.…”

mentioning

confidence: 99%

Novel Spray Freeze-Drying Technique Using Four-Fluid Nozzle-Development of Organic Solvent System to Expand Its Application to Poorly Water Soluble Drugs

Niwa

Shimabara

Danjo

2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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A significant number of active pharmaceutical ingredients (APIs) being discovered exhibit expected therapeutic behaviors, but unfortunately have undesirable drug-like properties such as low solubility and poor ADME performance, making formulation into an effective drug product challenging. In fact, more than 40% of the pharmaceutical candidates in the development pipelines are reported to be categorized as poorly soluble.1,2) These compounds are classified as biopharmaceutical classification system (BCS) class II for which their maximum bioavailability is limited by their rate of dissolution. 3,4) Improving the dissolution rate of these compounds is achieved through various approaches of formulation technology. These include particle size reduction/ milling, [5][6][7][8] solution-based precipitation, solid dispersion by hot melt extrusion 9) or spray-drying, 10,11) complexation with cyclodextrins 12,13) and so on, as also described extensively in reviews. 14,15) Cryogenic technologies such as freeze drying 16) and spray freezing into liquid (SFL), [17][18][19] in particular, have lately attracted considerable attention for BCS class II compounds. These processes use cryogen, particularly liquid nitrogen, to form a solid dispersion composed of nano-dispersed domains of API within the hydrophilic polymer matrix. In order to increase universality of unique lyophilization technique in SFL, authors have developed spray freeze-drying (SFD) technique before, which is combined the conventional spraydryer with freeze-dryer, both equipments are available in market. 20) In addition, SFD technique was further improved by adopting four-fluid nozzle (4N) to expand its application in pharmaceutical industry. 21) In the conventional process both API and a hydrophilic excipient, called drug and carrier in this report respectively, are necessary to be dissolved in common spray solution because two-fluid nozzle (2N) has only one liquid-supplying line. Using a common solvent would sometimes lead to restricted combination between API and the carrier. 4N having two liquid passages allows API and the carrier to be dissolved in separate solvents, overcoming this problem. In this research, the organic/aqueous co-solvent spray system was newly established in 4N-SFD process in which the poorly water-soluble drug was dissolved in organic solvent and the dissolution-modified carrier was dissolved in water, which is likely frequent combination for solubilization. Acetonitrile was selected as an organic spray solvent due to its good solvent property for many drugs, its relatively high melting point (Ϫ43.8°C) among organic solvents and its easily evaporated behavior with higher vapor pressure. Phenytoin and ciclosporin were used as a poorly water-soluble drug and two types of carrier were used as a dissolution modifier. In case using phenytoin, which is dissolved in aqueous alkaline solution as well as acetonitrile, 1) aqueous spray system (phenytoin dissolved in aqueous alkaline solution and the carrier dissolved in water; called 4N-SFD-aqua)...

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“…Technologies that have been commonly used to achieve this task include mechanical milling, 1) coprecipitation, 2,3) spray-drying, 4) the complex formation with watersoluble excipients, 5) and freeze-drying. 6) Spray drying has also been widely used as a technique to improve water solubility.…”

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confidence: 99%

Particle Characterization of Poorly Water-Soluble Drugs Using a Spray Freeze Drying Technique

Kondo

Niwa

Okamoto

et al. 2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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657Many newly developing compounds have been dropped out during the early stages of drug development process because of poorly water-soluble property. Poorly water-soluble drugs often demonstrate the low bioavailability when administered orally due to the low dissolution and absorption rate in the gastrointestinal tract. Therefore, improvement of the solubility of poorly water-soluble compounds is an important mission in drug development.Increasing the solubility and dissolution rate of poorly water-soluble drugs is a significant challenge to pharmaceutical scientists. Technologies that have been commonly used to achieve this task include mechanical milling, 1) coprecipitation, 2,3) spray-drying, 4) the complex formation with watersoluble excipients, 5) and freeze-drying. 6) Spray drying has also been widely used as a technique to improve water solubility. However, it is not always appropriate for thermolabile compounds because the spray-drying process requires elevated temperatures. Although lyophilization or freeze-drying is a promising technique to produce pharmaceutical powders with improved solubility, the freezing rate is so slow that this technique is often difficult to apply in the pharmaceutical industry.Spray freezing into liquid nitrogen (SFL) is a novel cryogenic atomization technology, developed by Williams et al. [7][8][9][10][11] in which either an aqueous or an aqueous-organic cosolvent solution containing an active pharmaceutical ingredient (API) and a pharmaceutical excipient is atomized directly into cryogenic liquid nitrogen. This method via atomization resulted in production of fine particles with a significant large specific surface area, with high yields, and has also been found to prevent interparticle aggregation. In addition, when insulin was atomized by this method, it was possible to obtain lower crystallinity while preventing protein aggregation.In our previous work, 12) the solid dispersions were prepared by rapidly cooling of melt drugs in ice or in liquid nitrogen, and it was found that liquid nitrogen was appropriate as a cryogenic source to prepare particle-shaped solid dispersion with amorphous drug. Based on these previous results, we devised new atomization with quick freezing drying (a novel spray freeze drying: SFD) process which combined the spray dryer with the freeze drying equipment. This SFD method is spraying the drug solution over the surface of liquid nitrogen using the nozzle of the spray drier unlike the SFL method. Mumenthaler and Leuenberger 13) use the spray dryer as well as us, however, the freezing temperature makes it freeze at Ϫ70-Ϫ90°C, comparatively high temperature.The objective of this study was to utilize SFD technology for the preparation of composite particles containing a watersoluble polymer and a poorly water-soluble drug. In addition, the particles obtained by SFD were physicochemically characterized in the viewpoint of solubility improvement. ExperimentalMaterials Tolbutamide (TBM), which was commercially purchased from Wako Pure Chemical Indust...

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Improved Dissolution of an Insoluble Drug Using a 4-Fluid Nozzle Spray-Drying Technique

Cited by 28 publications

References 29 publications

Scaling Up the Spray Drying Process from Pilot to Production Scale Using an Atomized Droplet Size Criterion

Scaling Up the Spray Drying Process from Pilot to Production Scale Using an Atomized Droplet Size Criterion

Novel Spray Freeze-Drying Technique Using Four-Fluid Nozzle-Development of Organic Solvent System to Expand Its Application to Poorly Water Soluble Drugs

Particle Characterization of Poorly Water-Soluble Drugs Using a Spray Freeze Drying Technique

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