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Pharmaceutics
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Drug Nanocrystals
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Drug Nanocrystals

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Nanomedicine and Nanotechnology".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 20254

Special Issue Editor

Dr. Leena Peltonen

E-Mail Website
Guest Editor
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, FI-00014 Helsinki, Finland
Interests: nanocrystals; nanoparticles; dissolution; solubility; physicochemical characterization
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pharmaceutical nanocrystal studies started in the beginning of the 1990s, and the first product entered the market after only 10 years of intensive research.  Today, the number of marketed products is increasing, products for different drug delivery routes exist, and solid formulations as well as suspensions can be found. The first applications were for improved solubility, and this is still the most well-known property of nanocrystal formulations, but today an increasing number of different applications like controlled release formulations are being studied, too. Accordingly, nanocrystals can be said to be a very versatile option for drug delivery purposes.

This Special Issue on nanocrystals will include a variety of research articles, both reviews and original research contributions, dealing with drug nanocrystals. From the production methods and process understanding to the fate of the nanocrystals in vivo, this Issue aims to provide an overview of well-established nanocrystallization techniques, marketed products, and promising new approaches in the modification of nanocrystals, for example, for controlled or targeted drug delivery applications in various routes of drug administration. All kind of contributions discussing the ability of nanocrystals for a wide variety of drug delivery purposes as well as limitations of the techniques are invited.

Dr. Leena Peltonen
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Production of drug nanocrystals
  • QbD approach, CQAs and process understanding for production of drug nanocrystals
  • Scaling up/scaling down, industrial applications of drug nanocrystals
  • Formulation studies with drug nanocrystals
  • Drug nanocrystal applications for different drug delivery routes
  • Fate in vivo and cell uptake of drug nanocrystals

Published Papers (7 papers)

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Research

9 pages, 1644 KiB  
Article
Nanocrystal Preparation of Poorly Water-Soluble Drugs with Low Metal Contamination Using Optimized Bead-Milling Technology
by Hironori Tanaka, Yuya Ochii, Yasushi Moroto, Daisuke Hirata, Tetsuharu Ibaraki and Ken-ichi Ogawara
Pharmaceutics 2022, 14(12), 2633; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14122633 - 28 Nov 2022
Viewed by 1248
Abstract
Nanocrystal preparation using bead milling is an important technology to enhance the solubility of poorly water-soluble drugs. However, there are safety concerns regarding the metal contaminants generated during bead milling. We have previously reported optimized bead-milling parameters that could minimize metal contamination and [...] Read more.
Nanocrystal preparation using bead milling is an important technology to enhance the solubility of poorly water-soluble drugs. However, there are safety concerns regarding the metal contaminants generated during bead milling. We have previously reported optimized bead-milling parameters that could minimize metal contamination and demonstrated comparable performance to NanoCrystal®, a world-leading contamination-free technology. This study aimed to investigate the applicability of optimized milling parameters for preparing nanocrystals of several poorly water-soluble drugs exhibiting various physicochemical properties. Using our optimized bead-milling parameters, we found that all the tested drugs could be ground into nanosized particles within 360 min. Notably, fenofibrate, which has a low melting point, could be ground into nanosized particles owing to the low level of heat generated during bead milling. Additionally, the concentration of metal contaminants in all the drugs prepared using the optimized milling parameters were approximately ten to twentyfold lower than those prepared without the optimized parameters and were comparable to those prepared using polycarbonate beads, known to minimize metal contamination during bead milling. Our results provide insights into the development of drug nanocrystals with low metal contamination using bead milling. Full article
(This article belongs to the Special Issue Drug Nanocrystals)
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20 pages, 3403 KiB  
Article
Excipient-Free Pure Drug Nanoparticles Fabricated by Microfluidic Hydrodynamic Focusing
by Roni Sverdlov Arzi, Asaf Kay, Yulia Raychman and Alejandro Sosnik
Pharmaceutics 2021, 13(4), 529; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13040529 - 10 Apr 2021
Cited by 8 | Viewed by 2568
Abstract
Nanoprecipitation is one of the most versatile methods to produce pure drug nanoparticles (PDNPs) owing to the ability to optimize the properties of the product. Nevertheless, nanoprecipitation may result in broad particle size distribution, low physical stability, and batch-to-batch variability. Microfluidics has emerged [...] Read more.
Nanoprecipitation is one of the most versatile methods to produce pure drug nanoparticles (PDNPs) owing to the ability to optimize the properties of the product. Nevertheless, nanoprecipitation may result in broad particle size distribution, low physical stability, and batch-to-batch variability. Microfluidics has emerged as a powerful tool to produce PDNPs in a simple, reproducible, and cost-effective manner with excellent control over the nanoparticle size. In this work, we designed and fabricated T- and Y-shaped Si-made microfluidic devices and used them to produce PDNPs of three kinase inhibitors of different lipophilicity and water-solubility, namely imatinib, dasatinib and tofacitinib, without the use of colloidal stabilizers. PDNPs display hydrodynamic diameter in the 90–350 nm range as measured by dynamic light scattering and a rounded shape as visualized by high-resolution scanning electron microscopy. Powder X-ray diffraction and differential scanning calorimetry confirmed that this method results in highly amorphous nanoparticles. In addition, we show that the flow rate of solvent, the anti-solvent, and the channel geometry of the device play a key role governing the nanoparticle size. Full article
(This article belongs to the Special Issue Drug Nanocrystals)
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13 pages, 3992 KiB  
Article
Synthesis and Characterization of Nano-Sized 4-Aminosalicylic Acid–Sulfamethazine Cocrystals
by Ala’ Salem, Anna Takácsi-Nagy, Sándor Nagy, Alexandra Hagymási, Fruzsina Gősi, Barbara Vörös-Horváth, Tomislav Balić, Szilárd Pál and Aleksandar Széchenyi
Pharmaceutics 2021, 13(2), 277; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13020277 - 19 Feb 2021
Cited by 10 | Viewed by 3114
Abstract
Drug–drug cocrystals are formulated to produce combined medication, not just to modulate active pharmaceutical ingredient (API) properties. Nano-crystals adjust the pharmacokinetic properties and enhance the dissolution of APIs. Nano-cocrystals seem to enhance API properties by combining the benefits of both technologies. Despite the [...] Read more.
Drug–drug cocrystals are formulated to produce combined medication, not just to modulate active pharmaceutical ingredient (API) properties. Nano-crystals adjust the pharmacokinetic properties and enhance the dissolution of APIs. Nano-cocrystals seem to enhance API properties by combining the benefits of both technologies. Despite the promising opportunities of nano-sized cocrystals, the research at the interface of nano-technology and cocrystals has, however, been described to be in its infancy. In this study, high-pressure homogenization (HPH) and high-power ultrasound were used to prepare nano-sized cocrystals of 4-aminosalysilic acid and sulfamethazine in order to establish differences between the two methods in terms of cocrystal size, morphology, polymorphic form, and dissolution rate enhancement. It was found that both methods resulted in the formation of form I cocrystals with a high degree of crystallinity. HPH yielded nano-sized cocrystals, while those prepared by high-power ultrasound were in the micro-size range. Furthermore, HPH produced smaller-size cocrystals with a narrow size distribution when a higher pressure was used. Cocrystals appeared to be needle-like when prepared by HPH compared to those prepared by high-power ultrasound, which had a different morphology. The highest dissolution enhancement was observed in cocrystals prepared by HPH; however, both micro- and nano-sized cocrystals enhanced the dissolution of sulfamethazine. Full article
(This article belongs to the Special Issue Drug Nanocrystals)
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14 pages, 3868 KiB  
Article
Self-Assembled Disulfide Bond Bearing Paclitaxel—Camptothecin Prodrug Nanoparticle for Lung Cancer Therapy
by Jingyan Gao, Xiaodong Ma, Lirong Zhang, Jiaqi Yan, Huaguang Cui, Yuezhou Zhang, Dongqing Wang and Hongbo Zhang
Pharmaceutics 2020, 12(12), 1169; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12121169 - 01 Dec 2020
Cited by 17 | Viewed by 3346
Abstract
Self-assembled prodrugs (SAPDs), which combine prodrug strategy and the merits of self-assembly, not only represent an appealing type of therapeutics, enabling the spontaneous organization of supramolecular nanocomposites with defined structures in aqueous environments, but also provide a new method to formulate existing drugs [...] Read more.
Self-assembled prodrugs (SAPDs), which combine prodrug strategy and the merits of self-assembly, not only represent an appealing type of therapeutics, enabling the spontaneous organization of supramolecular nanocomposites with defined structures in aqueous environments, but also provide a new method to formulate existing drugs for more favorable outcomes. To increase drug loading and combination therapy, we covalently conjugated paclitaxel (PTX) and camptothecin (CPT) through a disulfide linker into a prodrug, designated PTX-S-S-CPT. The successful production of PTX-S-S-CPT prodrug was confirmed by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). This prodrug spontaneously undergoes precipitation in aqueous surroundings. Taking advantage of a flow-focusing microfluidics platform, the prodrug nanoparticles (NPs) have good monodispersity, with good reproducibility and high yield. The as-prepared prodrug NPs were characterized with dynamic light scattering (DLS) and transmission electron microscopy (TEM), demonstrating spherical morphology of around 200 nm in size. In the end, the self-assembled NPs were added to mouse embryonic fibroblast (MEF), mouse lung adenocarcinoma and Lewis lung carcinoma (LLC) cell lines, and human non-small cell lung cancer cell line A549 to evaluate cell viability and toxicity. Due to the redox response with a disulfide bond, the PTX-S-S-CPT prodrug NPs significantly inhibited cancer cell growth, but had no obvious toxicity to healthy cells. This prodrug strategy is promising for co-delivery of PTX and CPT for lung cancer treatment, with reduced side effects on healthy cells. Full article
(This article belongs to the Special Issue Drug Nanocrystals)
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24 pages, 4200 KiB  
Article
Comparison of Downstream Processing of Nanocrystalline Solid Dispersion and Nanosuspension of Diclofenac Acid to Develop Solid Oral Dosage Form
by Sanika Jadhav, Amanpreet Kaur and Arvind Kumar Bansal
Pharmaceutics 2020, 12(11), 1015; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12111015 - 23 Oct 2020
Cited by 6 | Viewed by 2505
Abstract
The conventional “top-down”, “bottom-up” and “combination” approaches of generating drug nanocrystals produce a “nanosuspension” (NS). It requires significant downstream processing for drying the liquid by suitable means followed by its granulation to develop an oral solid dosage form (OSD). In this paper, we [...] Read more.
The conventional “top-down”, “bottom-up” and “combination” approaches of generating drug nanocrystals produce a “nanosuspension” (NS). It requires significant downstream processing for drying the liquid by suitable means followed by its granulation to develop an oral solid dosage form (OSD). In this paper, we used a novel, spray drying-based NanoCrySP technology for the generation of drug nanocrystals in the form of nanocrystalline solid dispersion (NCSD). We hypothesized that the NCSD would require minimal downstream processing since the nanocrystals are obtained in powder form during spray drying. We further compared downstream processing of NS and NCSD of diclofenac acid (DCF) prepared by wet media milling and NanoCrySP technology, respectively. The NS and NCSD were characterized for crystallinity, crystal size, assay and dissolution. The NCSD was physically mixed with 0.3% Aerosil® 200, 1.76% croscarmellose sodium (CCS) and 0.4% sodium stearyl fumarate (SSF) and filled into size 0 hard gelatin capsules. The NS was first wet granulated using Pearlitol® SD 200 (G1 granules) and Celphere® 203 (G2 granules) in a fluidized bed processor, and the resulting granules were mixed using the same extra granular excipients as NCSD and filled into capsules. A discriminatory dissolution method was developed to monitor changes in dissolution behavior due to crystal growth during processing. Cost analysis and comparison of process efficiency was performed using an innovation radar tool. The NS and NCSD were successfully fabricated with a crystal size of 363 ± 21.87 and 361.61 ± 11.78, respectively. In comparison to NCSD-based capsules (65.13%), the G1 and G2 granules showed crystal growth and decrease in dissolution to 52.68% and 48.37%, respectively, in 120 min. The overall cost for downstream processing of NCSD was up to 80% lower than that of NS. An innovation radar tool also concluded that the one-step NanoCrySP technology was more efficient and required less downstream processing than the two-step wet media milling approach for conversion of nanocrystals to OSD. Full article
(This article belongs to the Special Issue Drug Nanocrystals)
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10 pages, 588 KiB  
Article
Production of Itraconazole Nanocrystal-Based Polymeric Film Formulations for Immediate Drug Release
by Anna Karagianni and Leena Peltonen
Pharmaceutics 2020, 12(10), 960; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12100960 - 13 Oct 2020
Cited by 14 | Viewed by 2806
Abstract
In order to improve the solubility properties of BCS class II drug itraconazole, fast dissolving oral polymeric film formulations based on itraconazole nanocrystals were produced. Drug nanocrystals were manufactured by the wet pearl milling technique. In polymeric film formulations, hydroxypropyl methyl cellulose (HPMC) [...] Read more.
In order to improve the solubility properties of BCS class II drug itraconazole, fast dissolving oral polymeric film formulations based on itraconazole nanocrystals were produced. Drug nanocrystals were manufactured by the wet pearl milling technique. In polymeric film formulations, hydroxypropyl methyl cellulose (HPMC) was used as a film forming polymer, and glycerin was used as a plasticizer. For nanocrystal suspensions and film formulations, thorough physicochemical characterization was performed, including particle sizing and size deviation, film appearance, weight variation, thickness, folding endurance, drug content uniformity, disintegration time, and dissolution profile. After milling, the nanoparticles were 369 nm in size with a PI value of 0.20. Nanoparticles were stable and after redispersion from film formulations, the particle size remained almost the same (330 nm and PI 0.16). The produced films were flexible, homogeneous, fast disintegrating, and drug release rate from both the nanosuspension and film formulations showed immediate release behavior. Based on the study, the film casting method for production of itraconazole nanocrystal based immediate release formulations is a good option for improved solubility. Full article
(This article belongs to the Special Issue Drug Nanocrystals)
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17 pages, 6220 KiB  
Article
Insight into the Formation of Glimepiride Nanocrystals by Wet Media Milling
by Djordje Medarević, Svetlana Ibrić, Elisavet Vardaka, Miodrag Mitrić, Ioannis Nikolakakis and Kyriakos Kachrimanis
Pharmaceutics 2020, 12(1), 53; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12010053 - 09 Jan 2020
Cited by 17 | Viewed by 3314
Abstract
Nanocrystal formation for the dissolution enhancement of glimepiride was attempted by wet media milling. Different stabilizers were tested and the obtained nanosuspensions were solidified by spray drying in presence of mannitol, and characterized regarding their redispersibility by dynamic light scattering, physicochemical properties by [...] Read more.
Nanocrystal formation for the dissolution enhancement of glimepiride was attempted by wet media milling. Different stabilizers were tested and the obtained nanosuspensions were solidified by spray drying in presence of mannitol, and characterized regarding their redispersibility by dynamic light scattering, physicochemical properties by differential scanning calorimetry (DSC), FT-IR spectroscopy, powder X-ray diffraction (PXRD), and scanning electron microcopy (SEM), as well as dissolution rate. Lattice energy frameworks combined with topology analysis were used in order to gain insight into the mechanisms of particle fracture. It was found that nanosuspensions with narrow size distribution can be obtained in presence of poloxamer 188, HPC-SL and Pharmacoat® 603 stabilizers, with poloxamer giving poor redispersibility due to melting and sticking of nanocrystals during spray drying. DSC and FT-IR studies showed that glimepiride does not undergo polymorphic transformations during processing, and that the milling process induces changes in the hydrogen bonding patterns of glimepiride crystals. Lattice energy framework and topology analysis revealed the existence of a possible slip plane on the (101) surface, which was experimentally verified by PXRD analysis. Dissolution testing proved the superior performance of nanocrystals, and emphasized the important influence of the stabilizer on the dissolution rate of the nanocrystals. Full article
(This article belongs to the Special Issue Drug Nanocrystals)
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