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Pharmaceutics
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Recent Progress in Solid Dispersion Technology 2.0
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Recent Progress in Solid Dispersion Technology 2.0

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Physical Pharmacy and Formulation".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 28032

Special Issue Editor

Dr. Kohsaku Kawakami

E-Mail Website
Guest Editor
Research Center for Macromolecules and Biomaterials, National Institute for Materials Science (NIMS), 1-2-1 Sengen, Tsukuba 305-0047, Ibaraki, Japan
Interests: solid dispersion; supersaturation; molecular assemblies; poorly soluble drugs; thermal analysis; polymorphism; solubilization
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

For over half a century, amorphous solid dispersion (ASD) has been recognized as a powerful formulation technology for improve oral absorption of poorly soluble drugs. In spite of this long history, novel important findings on ASD continue to be reported every year. In contrast to other solubilization technologies using additives—including surfactants, cyclodextrins, and organic solvents, which increase equilibrium solubility—amorphization does not disturb membrane permeation process. Thus, the probability of success in improvement of oral absorption is considered generally high for ASDs. In 2019, a Special Issue entitled “Recent Progress in Solid Dispersion Technology” was published to cover the cutting-edge research in this field. We have decided to publish an updated version to keep up with the new knowledge and technologies that have since emerged in ASD research.

This Special Issue welcomes any topics regarding recent progress in ASD technology, including, but not limited to:

  • Prediction of oral absorption of drugs from ASDs;
  • Prediction of long-term storage stability of ASDs;
  • Relationship between compound property and its suitability for ASD;
  • How to maintain supersaturated state after dissolution of ASDs;
  • Novel manufacturing technologies involving ASD;
  • Novel functional carriers for ASD;
  • Novel analysis technologies for ASDs.

Dr. Kohsaku Kawakami
Guest Editor

Manuscript Submission Information

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Keywords

  • amorphous
  • solid dispersion
  • poorly soluble drug
  • supersaturation
  • crystallization
  • stability
  • spray-drying
  • hot-melt extrusion

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Published Papers (7 papers)

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Research

24 pages, 5355 KiB  
Article
Co-Spray Drying of Paracetamol and Propyphenazone with Polymeric Binders for Enabling Compaction and Stability Improvement in a Combination Tablet
by Ioannis Partheniadis, Ioannis Nikolakakis, Constantinos K. Zacharis, Kyriakos Kachrimanis and Nizar Al-Zoubi
Pharmaceutics 2021, 13(8), 1259; https://doi.org/10.3390/pharmaceutics13081259 - 14 Aug 2021
Cited by 2 | Viewed by 3317
Abstract
Paracetamol (PCT) and propyphenazone (PRP) are analgesic drugs that are often combined in a single dosage form for enhanced pharmacological action. In this work, PCT and PRP were co-spray dried separately with hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) using drug suspensions in [...] Read more.
Paracetamol (PCT) and propyphenazone (PRP) are analgesic drugs that are often combined in a single dosage form for enhanced pharmacological action. In this work, PCT and PRP were co-spray dried separately with hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) using drug suspensions in polymer solutions as feed liquids. It was thought that because of polymer adherence to the surface of drug particles, the risk of PCT–PRP contact and interaction could be reduced. Such interaction may be caused by localized temperature gradients due to frictional forces during tableting, or during storage under harsh conditions. A worst-case scenario would be eutectic formation due to variations in powder mixture homogeneity since eutectic and therapeutic mass PCT/PRP ratios are close (65:35 and 60:40, respectively) and eutectic temperature is low (~56 °C). Uniform particle size, round shape, compaction improvement and faster release of the analgesics were important additional benefits of co-spray drying. Experimental design was first applied for each drug to optimize the polymer concentration on the yield of spray drying and melting point separation (Δmp) of heated binary mixtures of co-spray dried PCT/neat PRP, and vice versa, with the two drugs always included at their therapeutic 60:40 ratio. Optimal combinations with largest Δmp and production yield were: co-spray dried PCT (15% HPC) with neat PRP and co-spray dried PRP (10% HPMC) with neat PCT. Compression studies of these combinations showed tableting improvement due to the polymers, as reflected in greater work of compaction and solid fraction, greater fracture toughness and tablet strength, easier tablet detachment from the punch surface and ejectability. Faster release of both drugs was obtained from the tablet of co-spray dried PCT (15% HPC) with neat PRP. A one-month stability test (75% RH/40 °C) showed moisture-induced alteration tablet strength. Full article
(This article belongs to the Special Issue Recent Progress in Solid Dispersion Technology 2.0)
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22 pages, 27339 KiB  
Article
Exploring the Role of Surfactants in Enhancing Drug Release from Amorphous Solid Dispersions at Higher Drug Loadings
by Sugandha Saboo, Pradnya Bapat, Dana E. Moseson, Umesh S. Kestur and Lynne S. Taylor
Pharmaceutics 2021, 13(5), 735; https://doi.org/10.3390/pharmaceutics13050735 - 17 May 2021
Cited by 40 | Viewed by 5650
Abstract
To reduce the dosage size of amorphous solid dispersion (ASD)-based formulations, it is of interest to devise formulation strategies that allow increased drug loading (DL) without compromising dissolution performance. The aim of this study was to explore how surfactant addition impacts drug release [...] Read more.
To reduce the dosage size of amorphous solid dispersion (ASD)-based formulations, it is of interest to devise formulation strategies that allow increased drug loading (DL) without compromising dissolution performance. The aim of this study was to explore how surfactant addition impacts drug release as a function of drug loading from a ternary ASD, using felodipine as a model poorly soluble compound. The addition of 5% TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate, a surfactant) to felodipine-polyvinylpyrrolidone/vinyl acetate ASDs was found to facilitate rapid and congruent (i.e., simultaneous) release of drug and polymer at higher DLs relative to binary ASDs (drug and polymer only). For binary ASDs, good release was observed for DLs up to <20% DL; this increased to 35% DL with surfactant. Microstructure evolution in ASD films following exposure to 100% relative humidity was studied using atomic force microscopy coupled with nanoscale infrared imaging. The formation of discrete, spherical drug-rich domains in the presence of surfactant appeared to be linked to systems showing congruent and rapid release of drug and polymer. In contrast, a contiguous drug-rich phase was formed for systems without surfactant at higher DLs. This study supports the addition of surfactant to ASD formulations as a strategy to increase DL without compromising release. Furthermore, insights into the potential role of surfactant in altering ASD release mechanisms are provided. Full article
(This article belongs to the Special Issue Recent Progress in Solid Dispersion Technology 2.0)
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17 pages, 2836 KiB  
Article
Multiparticulate Systems of Ezetimibe Micellar System and Atorvastatin Solid Dispersion Efficacy of Low-Dose Ezetimibe/Atorvastatin on High-Fat Diet-Induced Hyperlipidemia and Hepatic Steatosis in Diabetic Rats
by Carlos Torrado-Salmerón, Víctor Guarnizo-Herrero, Joana Henriques, Raquel Seiça, Cristina M. Sena and Santiago Torrado-Santiago
Pharmaceutics 2021, 13(3), 421; https://doi.org/10.3390/pharmaceutics13030421 - 20 Mar 2021
Cited by 8 | Viewed by 3417
Abstract
The aim of this study was to develop multiparticulate systems with a combination of ezetimibe micellar systems and atorvastatin solid dispersions using croscarmellose as a hydrophilic vehicle and Kolliphor RH40 as a surfactant. The presence of a surfactant with low hydrophilic polymer ratios [...] Read more.
The aim of this study was to develop multiparticulate systems with a combination of ezetimibe micellar systems and atorvastatin solid dispersions using croscarmellose as a hydrophilic vehicle and Kolliphor RH40 as a surfactant. The presence of a surfactant with low hydrophilic polymer ratios produces the rapid dissolution of ezetimibe through a drug–polymer interaction that reduces its crystallinity. The solid dispersion of atorvastatin with low proportions of croscarmellose showed drug–polymer interactions sufficient to produce the fast dissolution of atorvastatin. Efficacy studies were performed in diabetic Goto-Kakizaki rats with induced hyperlipidemia. The administration of multiparticulate systems of ezetimibe and atorvastatin at low (2 and 6.7 mg/kg) and high (3 and 10 mg/kg) doses showed similar improvements in levels of cholesterol, triglycerides, lipoproteins, alanine transaminase, and aspartate transaminase compared to the high-fat diet group. Multiparticulate systems at low doses (2 and 6.7 mg/kg of ezetimibe and atorvastatin) had a similar improvement in hepatic steatosis compared to the administration of ezetimibe and atorvastatin raw materials at high doses (3 and 10 mg/kg). These results confirm the effectiveness of solid dispersions with low doses of ezetimibe and atorvastatin to reduce high lipid levels and hepatic steatosis in diabetic rats fed a high-fat diet. Full article
(This article belongs to the Special Issue Recent Progress in Solid Dispersion Technology 2.0)
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16 pages, 4128 KiB  
Article
Applicability of an Experimental Grade of Hydroxypropyl Methylcellulose Acetate Succinate as a Carrier for Formation of Solid Dispersion with Indomethacin
by Hiroshi Ueda, Yuya Hirakawa, Hironori Tanaka, Tetsuya Miyano and Katsuji Sugita
Pharmaceutics 2021, 13(3), 353; https://doi.org/10.3390/pharmaceutics13030353 - 8 Mar 2021
Cited by 12 | Viewed by 2459
Abstract
The transformation of a crystalline drug into an amorphous form is a promising way to enhance the oral bioavailability of poorly water-soluble drugs. Blending of a carrier, such as a hydrophilic polymer, with an amorphous drug is a widely used method to produce [...] Read more.
The transformation of a crystalline drug into an amorphous form is a promising way to enhance the oral bioavailability of poorly water-soluble drugs. Blending of a carrier, such as a hydrophilic polymer, with an amorphous drug is a widely used method to produce a solid dispersion and inhibit crystallization. This study investigates an experimental grade of hydroxypropyl methylcellulose acetate succinate, HPMCAS-MX (MX), as a solid dispersion carrier. Enhancement of thermal stability and reduction of the glass transition temperature (Tg) of MX compared with those of the conventional grade were evaluated through thermogravimetric analysis and differential scanning calorimetry (DSC). The formation of a homogeneous amorphous solid dispersion between MX and indomethacin was confirmed by X-ray powder diffraction analysis, DSC, and Raman mapping. It was observed that 10–30% MX did not act as an anti-plasticizer, but the utilization of >40% MX caused an increase in Tg and reduction of molecular mobility. This could be explained by a change in intermolecular interactions, inferred from infrared spectroscopy combined with principal component analysis. HPMCAS-MX exhibited similar performance to that of conventional-grade, HPMCAS-MG. Although HPMCAS-MX has thermal properties different from those of conventional-grade HPMCAS-MG, it retains its ability as a solid dispersion carrier. Full article
(This article belongs to the Special Issue Recent Progress in Solid Dispersion Technology 2.0)
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13 pages, 3783 KiB  
Article
Relevance of Liquid-Liquid Phase Separation of Supersaturated Solution in Oral Absorption of Albendazole from Amorphous Solid Dispersions
by Kyosuke Suzuki, Kohsaku Kawakami, Masafumi Fukiage, Michinori Oikawa, Yohei Nishida, Maki Matsuda and Takuya Fujita
Pharmaceutics 2021, 13(2), 220; https://doi.org/10.3390/pharmaceutics13020220 - 5 Feb 2021
Cited by 14 | Viewed by 3549
Abstract
Amorphous solid dispersion (ASD) is one of the most promising formulation technologies for improving the oral absorption of poorly soluble drugs, where the maintenance of supersaturation plays a key role in enhancing the absorption process. However, quantitative prediction of oral absorption from ASDs [...] Read more.
Amorphous solid dispersion (ASD) is one of the most promising formulation technologies for improving the oral absorption of poorly soluble drugs, where the maintenance of supersaturation plays a key role in enhancing the absorption process. However, quantitative prediction of oral absorption from ASDs is still difficult. Supersaturated solutions can cause liquid-liquid phase separation through the spinodal decomposition mechanism, which must be adequately comprehended to understand the oral absorption of drugs quantitatively. In this study, albendazole (ALZ) was formulated into ASDs using three types of polymers, poly(methacrylic acid-co-methyl methacrylate) (Eudragit) L100, Vinylpyrrolidone-vinyl acetate copolymer (PVPVA), and hydroxypropyl methylcellulose acetate succinate (HPMCAS). The oral absorption of ALZ in rats administered as ASD suspensions was not explained by dissolution study but was predicted using liquid-liquid phase separation concentration, which suggested that the absorption of ALZ was solubility-limited. The oral administration study in dogs performed using solid capsules demonstrated the low efficacy of ASDs because the absorption was likely to be limited by dissolution rate, which indicated the importance of designing the final dosage form of the ASDs. Full article
(This article belongs to the Special Issue Recent Progress in Solid Dispersion Technology 2.0)
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15 pages, 4163 KiB  
Article
How Does the Addition of Kollidon®VA64 Inhibit the Recrystallization and Improve Ezetimibe Dissolution from Amorphous Solid Dispersions?
by Joanna Szafraniec-Szczęsny, Agata Antosik-Rogóż, Mateusz Kurek, Karolina Gawlak, Anna Górska, Sebastian Peralta, Justyna Knapik-Kowalczuk, Daniel Kramarczyk, Marian Paluch and Renata Jachowicz
Pharmaceutics 2021, 13(2), 147; https://doi.org/10.3390/pharmaceutics13020147 - 23 Jan 2021
Cited by 21 | Viewed by 4641
Abstract
Amorphization serves as a strategy for the improvement of poor dissolution characteristics of many drug compounds. However, in many formulations the content of polymeric stabilizer is high, which is undesirable from the perspective of future applications. Thus, studying the composition-dependent stability of amorphous [...] Read more.
Amorphization serves as a strategy for the improvement of poor dissolution characteristics of many drug compounds. However, in many formulations the content of polymeric stabilizer is high, which is undesirable from the perspective of future applications. Thus, studying the composition-dependent stability of amorphous solid dispersions seems to be demanded. In this paper, we describe the amorphization of ezetimibe, a lipid-lowering drug, in the spray drying process and investigate the effect of polyvinylpyrrolidone-co-poly(vinyl acetate) (PVP/VA) content on the physical stability and dissolution characteristics of the drug. Fully amorphous systems were obtained when the concentration of the polymer in solid dispersion was as low as 20%. The amorphization led to the dissolution enhancement by even 70%, with a noticeable sudden increase at around 40% of PVP/VA content and very small variations for systems having 66–90% PVP/VA. It was also correlated to wettability characteristics of solid dispersions, which may suggest that in the vicinity of 40% of the polymer content, the behavior of the system becomes independent of the PVP/VA content. Full article
(This article belongs to the Special Issue Recent Progress in Solid Dispersion Technology 2.0)
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21 pages, 2460 KiB  
Article
Enhancement of the Physical Stability of Amorphous Sildenafil in a Binary Mixture, with either a Plasticizing or Antiplasticizing Compound
by Justyna Knapik-Kowalczuk, Krzysztof Chmiel, Justyna Pacułt, Klaudia Bialek, Lidia Tajber and Marian Paluch
Pharmaceutics 2020, 12(5), 460; https://doi.org/10.3390/pharmaceutics12050460 - 18 May 2020
Cited by 12 | Viewed by 3683
Abstract
The main purpose of this paper was to evaluate the impact of both high- and low-Tg polymer additives on the physical stability of an amorphous drug, sildenafil (SIL). The molecular mobility of neat amorphous SIL was strongly affected by the polymeric excipients [...] Read more.
The main purpose of this paper was to evaluate the impact of both high- and low-Tg polymer additives on the physical stability of an amorphous drug, sildenafil (SIL). The molecular mobility of neat amorphous SIL was strongly affected by the polymeric excipients used (Kollidon VA64 (KVA) and poly(vinylacetate) (PVAc)). The addition of KVA slowed down the molecular dynamics of amorphous SIL (antiplasticizing effect), however, the addition of PVAc accelerated the molecular motions of the neat drug (plasticizing effect). Therefore, in order to properly assess the effect of the polymer on the physical stability of SIL, the amorphous samples at both: isothermal (at constant temperature—353 K) and isochronal (at constant relaxation time—τα = 1.5 ms) conditions were compared. Our studies showed that KVA suppressed the recrystallization of amorphous SIL more efficiently than PVAc. KVA improved the physical stability of the amorphous drug, regardless of the chosen concentration. On the other hand, in the case of PVAc, a low polymer content (i.e., 25 wt.%) destabilized amorphous SIL, when stored at 353 K. Nevertheless, at high concentrations of this excipient (i.e., 75 wt.%), its effect on the amorphous pharmaceutical seemed to be the opposite. Therefore, above a certain concentration, the PVAc presence no longer accelerates the SIL recrystallization process, but inhibits it. Full article
(This article belongs to the Special Issue Recent Progress in Solid Dispersion Technology 2.0)
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