Submit to Processes Review for Processes Edit a Special Issue

Journal Browser

► Journal Browser

Special Issue "Particulate Processes in the Formulation of Pharmaceuticals, Nutraceuticals and Bioactive Compounds"

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of Processes (ISSN 2227-9717). This special issue belongs to the section "Pharmaceutical Processes".

Deadline for manuscript submissions: closed (15 September 2022) | Viewed by 54044

Share This Special Issue

Special Issue Editors

Prof. Dr. Ioannis Nikolakakis

E-Mail Website
Guest Editor

Department of Pharmaceutical Technology, Faculty of Health Sciences, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
Interests: drug formulation; characterization of dosage forms; formulation of natural products with therapeutic perspectives
Special Issues, Collections and Topics in MDPI journals

Dr. Nizar Al-Zoubi

E-Mail Website
Guest Editor

Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Hashemite University, Zarqa, Jordan
Interests: development and evaluation of pharmaceutical formulations and excipients; particle engineering and characterization

Special Issue Information

Dear Colleagues,

Particulate processes producing particles in size scales from nanometers to millimeters play a major role in health sciences and the product market. This is because about 60% of marketed pharmaceuticals are solid dosage forms and about the same percentage of the overall nutraceutical consumption is accounted by dry excipients. The large number of orally administered poorly water-soluble drugs has necessitated the development of modern particle engineering processes aiming for improvement of solubility, permeability, and targeting effectiveness. Nanomilling, high-pressure homogenization, self-emulsification, and solid-lipid technology give particles in the nanosize range; spray-drying, freeze drying, and freeze spraying into liquid give composite microparticles in the micrometers range; electrospinning, electrospraying, and hot melt extrusion are able to produce drugs in the form of pharmaceutical salts, cocrystals, amorphous and co-amorphous drug systems, which after mechanical milling give particles in an intermediate size range of 10–100 μm. Finally, wet and dry granulation, melt granulation, and extrusion/spheronization are widely applied to give a free-flowing powder product split into multiple-unit dosage forms where the dose is subdivided into units of millimeter size particles with therapeutic and technological benefits. Similar considerations as set above apply to nutraceuticals with therapeutic properties, such as essential oils, prebiotics, and probiotics and other microorganisms, e.g., vaccines.

This Special Issue welcomes contributions of original research work and reviews reporting established and emerging technologies of particle engineering, the application of which leads to improvements in the properties of the particulate products, namely in the solubility, redispersibility, release, and permeability of the bioactive compound, handling (packing ability and flowability), compressibility and compactibility, swelling, matrix forming ability, and suitability for thermal processing. Application of mathematical models to describe the mechanisms and kinetics of particle formation, critical process factors involved in product quality and production yield, novel methods of particle structure, and solid-state characterization are encouraged.

Assoc. Prof. Dr. Ioannis Nikolakakis
Assoc. Prof. Dr. Nizar Al-Zoubi
Guest Editors

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. Processes 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 2000 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

particle technology
encapsulation
controlled drug delivery
targeting
protein drugs
cospray drying
cogrinding
processability
dissolution

Published Papers (13 papers)

Download All Papers

Editorial

Jump to: Research, Review

Open AccessEditorial

Special Issue on “Particulate Processes in the Formulation of Pharmaceuticals, Nutraceuticals and Bioactive Compounds”

Ioannis Nikolakakis

Processes 2023, 11(2), 308; https://doi.org/10.3390/pr11020308 - 17 Jan 2023

Viewed by 587

Abstract

Introduction [...] Full article

(This article belongs to the Special Issue Particulate Processes in the Formulation of Pharmaceuticals, Nutraceuticals and Bioactive Compounds)

Research

Jump to: Editorial, Review

Open AccessFeature PaperEditor’s ChoiceArticle

A Continuous Conical-Mill Operation for Dry Coating of Pharmaceutical Powders: The Role of Processing Time

William Roy

Inès Esma Achouri

Sophie Hudon

Jean-Sébastien Simard

and

Nicolas Abatzoglou

Processes 2022, 10(3), 540; https://doi.org/10.3390/pr10030540 - 09 Mar 2022

Cited by 1 | Viewed by 1257

Abstract

Over the last decade, the conical mill has emerged as a potential piece of equipment to use for continuous dry coating pharmaceutical powders. In this work, silicon dioxide was used as a guest particle on two excipients, fast flow lactose (FFL) and grade PH200 microcrystalline cellulose (MCC), for dry coating by a conical mill with a modified screen that permitted batch and continuous mode operation. Samples were pre-processed in a V-blender. SEM images, particle size distribution, and EDS mapping were used to characterise the treated powders. Pre-processed samples showed some discrete coating of the host particle. After batch processing, the samples were covered with a complete coating. When processed at high impeller speed, coating of FFL was a mix of A200P and FFL fines generated by attrition. Continuous mode processed samples, which had a lower processing time, were coated discretely and showed a better coating than the pre-processed samples. Increasing guest/host mass ratio with FFL host particle had a positive impact on the quality of the coating. These results help to build the case that the processing time of the conical mill is a key parameter to the success of the conical mill as dry coating equipment in the pharmaceutical industry. Full article

(This article belongs to the Special Issue Particulate Processes in the Formulation of Pharmaceuticals, Nutraceuticals and Bioactive Compounds)

► Show Figures

Figure 1

Open AccessFeature PaperArticle

Moisture Transport Coefficients Determination on a Model Pharmaceutical Tablet

Komlan Koumbogle

François Gitzhofer

and

Nicolas Abatzoglou

Processes 2022, 10(2), 254; https://doi.org/10.3390/pr10020254 - 27 Jan 2022

Cited by 2 | Viewed by 1622

Abstract

In this work, a novel methodology to determine moisture transport coefficients for MMC PH101 tablets is presented. Absolute permeability, moisture diffusion, moisture transfer, and water vapor permeability coefficients were estimated on compressed powder tablets produced with different compression pressures (20 MPa to 200 MPa with an interval of 20 MPa). The ASTM D6539 standard test was used to measure the absolute permeability. The moisture transfer coefficient was determined from measured absolute permeability. The moisture diffusion coefficient was obtained with the tablet average pore radius, which was determined with the water droplet penetration method. Descriptive and phenomenological models derived from the measurements were confronted with existing and adopted models, and a good agreement was found. The obtained models are of the function of the microstructural properties of the tablet (average pore radius and average porosity). The tablet average porosity was found to be the principal parameter that governs the behavior of the moisture transport coefficients. The findings of this study might be applicable to obtain a series of input parameters for modelling software, such as COMSOL Multiphysics^®, to infer delamination, sticking, and failure propensity from the effect of moisture. Full article

(This article belongs to the Special Issue Particulate Processes in the Formulation of Pharmaceuticals, Nutraceuticals and Bioactive Compounds)

► Show Figures

Figure 1

Open AccessFeature PaperEditor’s ChoiceArticle

Development of a Nanocrystal Formulation of a Low Melting Point API Following a Quality by Design Approach

Andreas Ouranidis

Nikos Gkampelis

Catherine Markopoulou

Ioannis Nikolakakis

and

Kyriakos Kachrimanis

Processes 2021, 9(6), 954; https://doi.org/10.3390/pr9060954 - 27 May 2021

Cited by 6 | Viewed by 2429

Abstract

Preparation of nanocrystal formulations by wet media milling and spray-drying is a reliable technique to enhance dissolution and ameliorate absorption limitations of poorly soluble BCS II drugs. However, when thermosensitive compositions are dried at high temperatures, the risks of particle aggregation and thermal degradation must be considered. The present study investigates the effects of nanosuspension formulation variables when performing the spray drying process at equidistant temperatures above and below the melting point. Towards this purpose, Fenofibrate is exploited as a model drug of unfavorable pharmacokinetic profile and low melting point (79–82 °C), properties that render thermal processing a nontrivial task. Rationalizing the system’s behavior by combining molecular simulations with QbD methodology, the preparation of stable nanocrystals can be “steered” in order to avoid undesirable melting. The statistically resolved operational conditions showed that Fenofibrate Critical Quality Attribute–compliant nanosuspensions i.e., bearing hydrodynamic diameter and ζ-potential of 887 nm and −16.49 mV, respectively, were obtained by wet milling drug to Pharmacoat and mannitol weighted optimum ratios of 4.075% and 0.75%, after spray drying at the desired temperature of 77 °C. In conclusion, we present a quality assurance methodology of nano-comminution generally applicable for thermo-labile BCS II drugs. Full article

(This article belongs to the Special Issue Particulate Processes in the Formulation of Pharmaceuticals, Nutraceuticals and Bioactive Compounds)

► Show Figures

Graphical abstract

Open AccessArticle

Cumulative Production of Bioactive Rg3, Rg5, Rk1, and CK from Fermented Black Ginseng Using Novel Aspergillus niger KHNT-1 Strain Isolated from Korean Traditional Food

Jin Kyu Park

Dong Uk Yang

Lakshminarayanan Arunkumar

Yaxi Han

Seung Jin Lee

Muhammad Huzaifa Arif

and

Processes 2021, 9(2), 227; https://doi.org/10.3390/pr9020227 - 26 Jan 2021

Cited by 6 | Viewed by 1999

Abstract

Ginseng is an ancient herb widely consumed due to its healing property of active ginsenosides. Recent researchers were explored to increase its absorption and bioavailability of ginsenosides at the metabolic sites, due to its pharmacological activity. The purpose of this study was to investigate the isolation and characteristics of components obtained by a shorter steaming cycle (seven cycles) of white ginseng to fermented black ginseng, using a novel strain of Aspergillus niger KHNT-1 isolated from fermented soybean. The degree of bioactive of Rg3 increased effectively during the steaming process, and biotransformation converted the color towards black along active ginsenosides. Glycol moiety associated with C-3, C-6, or C-20 underwent rapid biotransformation and hydrolysis, such as Rb1, Rb2, Rc, Rd → Rg3, F2, and was converted to CK. Dehydration produces Rg3 → Rk1, Rg5. Rh2 → Rk2; thus, converted fermented black ginseng was solvent-extracted, and the isolated components were identified by TLC, HPLC, and quantification by LCMS. The unique composition obtained during this process with Rk1, Rg3, Rg5, and CK is nontoxic to HaCaT cell line up to 200 ug/mL for 24 h and was found to be effective in B16BL6 cell lines, in a dose- and time-dependent manner. Thus, it is a suitable candidate for nutraceuticals and cosmeceuticals. Full article

(This article belongs to the Special Issue Particulate Processes in the Formulation of Pharmaceuticals, Nutraceuticals and Bioactive Compounds)

► Show Figures

Graphical abstract

Open AccessFeature PaperArticle

Impact of Hot-Melt-Extrusion on Solid-State Properties of Pharmaceutical Polymers and Classification Using Hierarchical Cluster Analysis

Ioannis Partheniadis

Miltiadis Toskas

Filippos-Michail Stavras

Georgios Menexes

and

Ioannis Nikolakakis

Processes 2020, 8(10), 1208; https://doi.org/10.3390/pr8101208 - 25 Sep 2020

Cited by 9 | Viewed by 3060

Abstract

The impact of hot-melt extrusion (HME) on the solid-state properties of four methacrylic (Eudragit^® L100-55, Eudragit^® EPO, Eudragit^® RSPO, Eudragit^® RLPO) and four polyvinyl (Kollidon^® VA64, Kollicoat^® IR, Kollidon^® SR, and Soluplus^®) polymers was studied. Overall, HME decreased Tg but increased electrostatic charge and surface free energy. Packing density decreased with electrostatic charge, whereas Carr’s and Hausner indices showed a peak curve dependency. Overall, HME reduced work of compaction (Wc), deformability (expressed as Heckel P_Y and Kawakita 1/b model parameters and as slope S′ of derivative force/displacement curve), and tablet strength (TS) but increased elastic recovery (ER). TS showed a better correlation with S′ than P_Y and 1/b. Principal component analysis (PCA) organized the data of neat and extruded polymers into three principal components explaining 72.45% of the variance. The first included Wc, S′ and TS with positive loadings expressing compaction, and ER with negative loading opposing compaction; the second included P_Y, 1/b, and surface free energy expressing interactivity with positive loadings opposing tap density or close packing. Hierarchical cluster analysis (HCA) assembled polymers of similar solid-state properties regardless of HME treatment into a major cluster with rescaled distance Cluster Combine Index (CCI) < 5 and several other weaker clusters. Polymers in the major cluster were: neat and extruded Eudragit^® RSPO, Kollicoat^® IR, Kollidon^® SR, Soluplus^®, and extruded Eudragit^® L100-55. It is suggested that PCA may be used to distinguish variables having similar or dissimilar activity, whereas HCA can be used to cluster polymers based on solid-state properties and pick exchangeable ones (e.g., for sustain release or dissolution improvement) when the need arises. Full article

(This article belongs to the Special Issue Particulate Processes in the Formulation of Pharmaceuticals, Nutraceuticals and Bioactive Compounds)

► Show Figures

Figure 1

Open AccessFeature PaperArticle

Fabrication of Biopolymer Based Nanoparticles for the Entrapment of Chromium and Iron Supplements

Nishay Patel

Mohammed Gulrez Zariwala

and

Hisham Al-Obaidi

Processes 2020, 8(6), 707; https://doi.org/10.3390/pr8060707 - 19 Jun 2020

Cited by 2 | Viewed by 2480

Abstract

The objective of this study was to encapsulate iron and chromium into novel nanoparticles formulated using chitosan (CS), dextran sulfate (DS) and whey protein isolate (WPI) for oral drug delivery. Empty and loaded CS-DS nanoparticles were prepared via complex coacervation whilst whey protein nanocarriers were produced by a modified thermal processing method using chitosan. The physiochemical properties of the particles were characterized to determine the effects of formulation variables, including biopolymer ratio on particle size and zeta potential. Permeability studies were also undertaken on the most stable whey protein–iron nanoparticles by measuring Caco-2 ferritin formation. A particle size analysis revealed that the majority of samples were sub-micron sized, ranging from 420–2400 nm for CS-DS particles and 220–1000 nm for WPI-CS samples. As expected, a higher chitosan concentration conferred a 17% more positive zeta potential on chromium-entrapped WPI nanoparticles, whilst a higher dextran volume decreased the size of CS-DS nanoparticles by 32%. The addition of iron also caused a significant increase in size for all samples, as seen where the loaded WPI samples were 296 nm larger than the empty particles. Caco-2 iron absorption revealed that one formulation, which had the lowest particle size (226 ± 10 nm), caused a 64% greater iron absorption compared to the ferrous sulfate standard. This study describes, for the first time, the novel design of chromium- and iron-entrapped nanoparticles, which could act as novel systems for oral drug delivery. Full article

(This article belongs to the Special Issue Particulate Processes in the Formulation of Pharmaceuticals, Nutraceuticals and Bioactive Compounds)

► Show Figures

Figure 1

Open AccessArticle

DEM Investigation of the Influence of Particulate Properties and Operating Conditions on the Mixing Process in Rotary Drums: Part 1—Determination of the DEM Parameters and Calibration Process

and

Processes 2020, 8(2), 222; https://doi.org/10.3390/pr8020222 - 14 Feb 2020

Cited by 36 | Viewed by 6033

Abstract

This paper’s goal was to select methods and a calibration procedure which would lead to the determination of relevant parameters of a discrete element method (DEM) and virtual material creation. Seven particulates were selected with respect to their shape (spherical and non-spherical), size and density. The first calibration experiment involved “packing test” to determine the shape accuracy and bulk density of virtual packed particulates. The series of simulations were compared with real experiments, and the size, shape and density of virtual particles were optimized. Using three apparatuses, the input parameter values were experimentally determined for a contact model that defines the behavior of particulates in DEM simulations. The research part of the paper examines the influence of factors such as particle number; pile formation method; and the method of evaluation of the angle of repose on the process of the calibration of virtual material. The most reproducible results were achieved by the “pilling” method and by the rotating drum—both evaluated by the geometric method. However, it is always advisable to make an overall visual comparison of the slope shape between the calibration simulation and the experimental curves. The bowl’s diameter to particle size ratio should be greater than 25, and the calibration experiment should contain approximately 4000 particles to ensure representative results during angle of repose calibration experiment. Full article

(This article belongs to the Special Issue Particulate Processes in the Formulation of Pharmaceuticals, Nutraceuticals and Bioactive Compounds)

► Show Figures

Graphical abstract

Open AccessArticle

DEM Investigation of the Influence of Particulate Properties and Operating Conditions on the Mixing Process in Rotary Drums: Part 2—Process Validation and Experimental Study

and

Processes 2020, 8(2), 184; https://doi.org/10.3390/pr8020184 - 05 Feb 2020

Cited by 18 | Viewed by 4426

Abstract

The process of homogenization of particulates is an indispensable part of many industrial processes, and, therefore, it is necessary to pay a special attention to this area and develop it. This paper deals with a complex study of homogenization of particulate matters in a rotary drum in terms of shape, size, and density of particles. In addition, the influence of operating parameters, such as drum filling capacity, rotational speed, and drum filling pattern are also investigated. Studies of reproducibility of discrete element method simulations, effects of rotary drum sizes or effects of drum volumetric filling to the mixture homogeneity index were also carried out. In general, the least satisfactory values of the homogeneity index resulted from the mixing of particles with different densities. The dominating factor of homogenization was the drum filling-up degree. The course of the homogeneity index in 140, 280, and 420 mm drums was very similar and after five revolutions of the drum, identical values of the homogeneity index were achieved for all the drum diameters. The optimal drum filling-up degree is at 40–50% for the spherical particles and 30–40% for the sharp-edged particles. The repeatability of simulations showed the maximum relative standard deviation of the homogeneity index at 0.6% from ten simulation repetitions with the same parametric conditions. Full article

(This article belongs to the Special Issue Particulate Processes in the Formulation of Pharmaceuticals, Nutraceuticals and Bioactive Compounds)

► Show Figures

Graphical abstract

Open AccessArticle

Taste Masking of Nizatidine Using Ion-Exchange Resins

Pattaraporn Panraksa

Kasidech Boonsermsukcharoen

Kyu-Mok Hwang

Eun-Seok Park

and

Pensak Jantrawut

Processes 2019, 7(11), 779; https://doi.org/10.3390/pr7110779 - 30 Oct 2019

Cited by 7 | Viewed by 3069

Abstract

The purpose of this study was to mask the bitter taste of nizatidine (NZD) using cation-exchange resins. Amberlite IRP-69 and Dowex-50 containing cross-linked polystyrene backbones were used. The drug resin complexes were prepared by batch process using drug: resin ratios of 1:1, 1:3, and 1:5. The optimum drug: resin ratio and the time required for maximum percentage drug loading into the complexes were determined. The selected drug-resin complexes were evaluated for morphology, drug release, and taste. The NZD-Dowex complex was obtained at a drug: resin ratio of 1:5 using a stirring time of 1 h in order to get 100% loading of NZD. The NZD-Dowex complex had a spherical shape and smooth texture similar to Dowex resin. The NZD-Dowex complex with a ratio of 1:5 showed that in vitro drug release of 4.27% at 5 min in simulated salivary fluid of pH 6.8 and 99.67% at 1 h in simulated gastric fluid of pH 1.2. NZD’s bitter taste was effectively masked when it formed a complex with Dowex at a ratio of 1:5. This was proved by an electronic tongue and human test panel. Full article

(This article belongs to the Special Issue Particulate Processes in the Formulation of Pharmaceuticals, Nutraceuticals and Bioactive Compounds)

► Show Figures

Figure 1

Review

Jump to: Editorial, Research

Open AccessFeature PaperReview

Spray Drying for Direct Compression of Pharmaceuticals

and

Processes 2021, 9(2), 267; https://doi.org/10.3390/pr9020267 - 30 Jan 2021

Cited by 14 | Viewed by 8210

Abstract

Tableting by direct compression (DC) is one of the simplest and most cost-effective drug manufacturing approaches. However, most active pharmaceutical ingredients (APIs) and excipients lack the compression and flow properties required to meet the needs of high-speed industrial tablet presses. Therefore, the majority of DC APIs and excipients are modified via processing/co-processing particle engineering techniques to boost their properties. Spray drying is one of the most commonly employed techniques to prepare DC grades of APIs and excipients with prominent advantages. This review aims to present an overview of the commercially marketed and investigationally-prepared DC APIs and excipients produced by spray drying. Full article

(This article belongs to the Special Issue Particulate Processes in the Formulation of Pharmaceuticals, Nutraceuticals and Bioactive Compounds)

► Show Figures

Figure 1

Open AccessReview

Spray Drying for the Preparation of Nanoparticle-Based Drug Formulations as Dry Powders for Inhalation

and

Processes 2020, 8(7), 788; https://doi.org/10.3390/pr8070788 - 06 Jul 2020

Cited by 40 | Viewed by 12444

Abstract

Nanoparticle-based therapeutics have been used in pulmonary formulations to enhance delivery of poorly water-soluble drugs, protect drugs against degradation and achieve modified release and drug targeting. This review focuses on the use of spray drying as a solidification technique to produce microparticles containing nanoparticles (i.e., nanoparticle (NP) agglomerates) with suitable properties as dry powders for inhalation. The review covers the general aspects of pulmonary drug delivery with emphasis on nanoparticle-based dry powders for inhalation and the principles of spray drying as a method for the conversion of nanosuspensions to microparticles. The production and therapeutic applications of the following types of NP agglomerates are presented: nanoporous microparticles, nanocrystalline agglomerates, lipid-based and polymeric formulations. The use of alternative spray-drying techniques, namely nano spray drying, and supercritical CO₂-assisted spray drying is also discussed as a way to produce inhalable NP agglomerates. Full article

(This article belongs to the Special Issue Particulate Processes in the Formulation of Pharmaceuticals, Nutraceuticals and Bioactive Compounds)

► Show Figures

Figure 1

Open AccessFeature PaperReview

A Mini-Review: Needleless Electrospinning of Nanofibers for Pharmaceutical and Biomedical Applications

and

Processes 2020, 8(6), 673; https://doi.org/10.3390/pr8060673 - 06 Jun 2020

Cited by 49 | Viewed by 4728

Abstract

Electrospinning (ES) is a convenient and versatile method for the fabrication of nanofibers and has been utilized in many fields including pharmaceutical and biomedical applications. Conventional ES uses a needle spinneret for the generation of nanofibers and is associated with many limitations and drawbacks (i.e., needle clogging, limited production capacity, and low yield). Needleless electrospinning (NLES) has been proposed to overcome these problems. Within the last two decades (2004–2020), many research articles have been published reporting the use of NLES for the fabrication of polymeric nanofibers intended for drug delivery and biomedical tissue engineering applications. The objective of the present mini-review article is to elucidate the potential of NLES for designing such novel nanofibrous drug delivery systems and tissue engineering constructs. This paper also gives an overview of the key NLES approaches, including the most recently introduced NLES method: ultrasound-enhanced electrospinning (USES). The technologies underlying NLES systems and an evaluation of electrospun nanofibers are presented. Even though NLES is a promising approach for the industrial production of nanofibers, it is a multivariate process, and more research work is needed to elucidate its full potential and limitations. Full article

(This article belongs to the Special Issue Particulate Processes in the Formulation of Pharmaceuticals, Nutraceuticals and Bioactive Compounds)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Special Issue "Particulate Processes in the Formulation of Pharmaceuticals, Nutraceuticals and Bioactive Compounds"

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (13 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI