Impact of Physicochemical Properties of Pharmaceutical Substances on Dosage Form Performance

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

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 49629

Special Issue Editors


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Guest Editor
Chair and Department of Pharmaceutical Technology, Poznan University of Medical Sciences, Poznan, Poland
Interests: new drug carriers (ordered mesoporous silica and electro-spun biodegradable polymer materials); preformulation and drug dissolution/release; manufacturing process of solid dosage forms

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Guest Editor
School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, College Green, 2 Dublin, Ireland
Interests: anti-crystal engineering (ionic liquids and eutectic forms of drugs); multicomponent and liquid crystals; amorphous pharmaceutical system; poorly soluble drugs

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Guest Editor
Institute of Chemical Technology and Engineering, Poznan University of Technology, Poznan, Poland
Interests: chromatographic techniques in materials characterisation

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Guest Editor
Chair and Department of Pharmaceutical Technology, Poznan University of Medical Sciences, Poznan, Poland
Interests: solid state of pharmaceuticals; amorphous pharmaceutical systems; multicomponent pharmaceutical systems; poorly soluble drugs; preformulation

Special Issue Information

Dear Colleagues,

The physicochemical properties of an active pharmaceutical ingredient (API) and/or an excipient may affect the development of a dosage form, regardless of its type and route of administration, and influence its performance. For instance, a success in the design of semi-solid dosage formulation is largely determined on understanding the physicochemical factors (e.g., solubility, partition coefficient) that modulate bioavailability, while in the case of solid oral dosage forms, poor solubility and low dissolution rates often lead to poor bioavailability. There are many approaches that could be used to improve drug solubility and dissolution rates, e.g., chemical modification of APIs, solid state alteration, the use of excipients (surfactants, cyclodextrins or polymers) or manipulation of particle size. The solid form, the particle size and shape of an API or excipient may have a significant impact on the properties of the final dosage form. When a therapeutically active molecule is under development, it is crucial that it is produced it in a desired form in a consistent, pure and reproducible manner. Furthermore, during the formulation process, the API can undergo physical and/or chemical changes. Despite a wide variety of analytical techniques available to characterise APIs, such as thermal analysis, spectroscopy and others, the structural characterisation of subtle differences between different solid-state forms (for example amorphous forms) of API continues to be a challenge. The physicochemical properties of a solid pharmaceutical substance are strongly related not only to its structural features but also to its molecular dynamics. Thus, it is important to understand not only the structure but also the dynamic of molecular motion occurring in a drug substance because molecular relaxation may take place during storage of the formulated drug. Therefore, a thorough knowledge of the solid-state behaviour of a pharmaceutical substance is essential for reliable drug product manufacturing.

This Special Issue welcomes contributions demonstrating the impact of physicochemical properties of pharmaceutical substances on dosage form performance. It aims at presenting the current status of the field and highlighting the prospects of this area of pharmaceutical sciences. As the topic is very relevant to the industrial drug product development process, we encourage submissions emerging from co-operation between academia and pharmaceutical industry.

Prof. Dr. Janina Lulek
Dr. Lidia Tajber
Prof. Dr. Adam Voelkel
Dr. Marcin Skotnicki
Guest Editors

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Keywords

  • active pharmaceutical ingredient
  • excipient
  • solid state form
  • particle size and shape
  • chemical and physical stability
  • solubility/dissolution rate
  • compatibility
  • preformulation/formulation

Published Papers (11 papers)

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Research

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12 pages, 3541 KiB  
Article
Oxidized Chitosan-Tobramycin (OCS-TOB) Submicro-Fibers for Biomedical Applications
by Zhen Li, Shunqi Mei, Yajie Dong, Fenghua She, Chengpeng Li, Yongzhen Li and Lingxue Kong
Pharmaceutics 2022, 14(6), 1197; https://doi.org/10.3390/pharmaceutics14061197 - 03 Jun 2022
Cited by 2 | Viewed by 1376
Abstract
Chitosan (CS) is a biodegradable, biocompatible, and non-toxic natural amino-poly-saccharide with antibacterial ability, owing to its positively charged amino groups. However, the low charge density leads to poor antibacterial efficiency which cannot meet the biomedical application requirements. In this study, Tobramycin (TOB) was [...] Read more.
Chitosan (CS) is a biodegradable, biocompatible, and non-toxic natural amino-poly-saccharide with antibacterial ability, owing to its positively charged amino groups. However, the low charge density leads to poor antibacterial efficiency which cannot meet the biomedical application requirements. In this study, Tobramycin (TOB) was grafted onto the backbone of oxidized chitosan (OCS) to synthesize oxidized chitosan-tobramycin (OCS-TOB). FTIR, 1H NMR and elemental analysis results demonstrated that OCS-TOB was successfully synthesized. OCS-TOB/PEO composite fibrous materials were produced by a self-made centrifugal spinning machine. In vitro experiments showed that cells proliferated on the submicro-fibrous OCS-TOB/PEO of appropriate concentration, and the antibacterial ability of OCS-TOB was much improved, compared with pristine CS. The results demonstrated that OCS-TOB/PEO nanofibrous materials could potentially be used for biomedical applications. Full article
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9 pages, 1221 KiB  
Article
The Effects of Various Food Products on Bisphosphonate’s Availability
by Monika Zielińska, Grzegorz Garbacz, Jaroslaw Sczodrok and Adam Voelkel
Pharmaceutics 2022, 14(4), 717; https://doi.org/10.3390/pharmaceutics14040717 - 27 Mar 2022
Cited by 1 | Viewed by 1544
Abstract
The bioavailability of orally administered bisphosphonates is very low (<1%) due to their short absorption window in the proximal duodenum and high affinity for food. Food ingredients are able to bind the drug, but the presence of food extends the residence time of [...] Read more.
The bioavailability of orally administered bisphosphonates is very low (<1%) due to their short absorption window in the proximal duodenum and high affinity for food. Food ingredients are able to bind the drug, but the presence of food extends the residence time of bisphosphonates in the absorption window. Therefore, the main goal of this study is to select a group of food products that are characterized by low binding affinity to bisphosphonates and thus will not reduce their availability upon concomitant administration. For this purpose, a combination of three methods was applied: (1) evaluation of sorption capacity for rows of digested food samples in a simulated intestinal environment; (2) evaluation of drug availability in simulated chyme; and (3) evaluation of drug availability using a simulating needle device. The results indicate that food products such as egg white and white bread are most suitable for consumption during oral bisphosphonate intake. Full article
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15 pages, 2454 KiB  
Article
Role of Cyclodextrins and Drug Solid State Properties on Flufenamic Acid Dissolution Performance from Tablets
by Francesca Maestrelli, Marzia Cirri, Enrico De Luca, Diletta Biagi and Paola Mura
Pharmaceutics 2022, 14(2), 284; https://doi.org/10.3390/pharmaceutics14020284 - 26 Jan 2022
Cited by 6 | Viewed by 2423
Abstract
Flufenamic acid (FFA) is a non-steroidal anti-inflammatory drug characterised by a low solubility and problems of variable dissolution rate and bio-inequivalence. Different FFA batches, obtained by different suppliers, showed different powder characteristics (particle size, shape and surface properties) that may affect its dissolution [...] Read more.
Flufenamic acid (FFA) is a non-steroidal anti-inflammatory drug characterised by a low solubility and problems of variable dissolution rate and bio-inequivalence. Different FFA batches, obtained by different suppliers, showed different powder characteristics (particle size, shape and surface properties) that may affect its dissolution behaviour from solid dosage forms. Aim of this work was the improvement of FFA solubility and dissolution rate by the use of cyclodextrins (CDs) and the obtainment of an effective tablet formulation by direct compression. Several CDs have been tested, both in solution and in solid state and several binary systems drug-CDs have been obtained with different techniques, with the scope to select the most effective system. Grinding technique with randomly methylated-β-cyclodextrin (RAMEB) was the only one that allowed the complete drug amorphization, together with the highest improvement in drug dissolution rate, and was then selected for tablets formulation. Conventional and immediate release tablets were obtained and fully characterised for technological properties. In both cases an improved and well reproducible drug dissolution performance was obtained, independently from the FFA supplier and thus no more affected by the differences observed between the original FFA crystalline samples. Full article
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18 pages, 1741 KiB  
Article
Optimization and Evaluation of the In Vitro Permeation Parameters of Topical Products with Non-Steroidal Anti-Inflammatory Drugs through Strat-M® Membrane
by Bartłomiej Milanowski, Hanna Wosicka-Frąckowiak, Eliza Główka, Małgorzata Sosnowska, Stanisław Woźny, Filip Stachowiak, Angelika Suchenek and Dariusz Wilkowski
Pharmaceutics 2021, 13(8), 1305; https://doi.org/10.3390/pharmaceutics13081305 - 20 Aug 2021
Cited by 14 | Viewed by 3630
Abstract
Pharmaceutical products containing non-steroidal anti-inflammatory drugs (NSAIDs) are among the most prescribed topical formulations used for analgesic and antirheumatic properties. These drugs must overcome the skin barrier to cause a therapeutic effect. Human skin has been widely used as a model to study [...] Read more.
Pharmaceutical products containing non-steroidal anti-inflammatory drugs (NSAIDs) are among the most prescribed topical formulations used for analgesic and antirheumatic properties. These drugs must overcome the skin barrier to cause a therapeutic effect. Human skin has been widely used as a model to study in vitro drug diffusion and permeation, however, it suffers from many limitations. Therefore, to perform in vitro permeation test (IVPT), we used a Strat-M® membrane with diffusion characteristics well-correlated to human skin. This study’s objective was to optimize the IVPT conditions using Plackett–Burman experimental design for bio-predictive evaluation of the in vitro permeation rates of five non-steroidal anti-inflammatory drugs (diclofenac, etofenamate, ibuprofen, ketoprofen, naproxen) across Strat-M® membrane from commercial topical formulations. The Plackett–Burman factorial design was used to screen the effect of seven factors in eight runs with one additional center point. This tool allowed us to set the sensitive and discriminative IVPT final conditions that can appropriately characterize the NSAIDs formulations. The permeation rate of etofenamate (ETF) across the Strat-M® membrane was 1.7–14.8 times faster than other NSAIDs from selected semisolids but 1.6 times slower than the ETF spray formulation. Full article
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29 pages, 6660 KiB  
Article
Pre-Formulation Studies: Physicochemical Characteristics and In Vitro Release Kinetics of Insulin from Selected Hydrogels
by Aneta Ostróżka-Cieślik, Małgorzata Maciążek-Jurczyk, Jadwiga Pożycka and Barbara Dolińska
Pharmaceutics 2021, 13(8), 1215; https://doi.org/10.3390/pharmaceutics13081215 - 06 Aug 2021
Cited by 7 | Viewed by 3206
Abstract
Insulin loaded to the polymer network of hydrogels may affect the speed and the quality of wound healing in diabetic patients. The aim of our research was to develop a formulation of insulin that could be applied to the skin. We chose hydrogels [...] Read more.
Insulin loaded to the polymer network of hydrogels may affect the speed and the quality of wound healing in diabetic patients. The aim of our research was to develop a formulation of insulin that could be applied to the skin. We chose hydrogels commonly used for pharmaceutical compounding, which can provide a form of therapy available to every patient. We prepared different gel formulations using Carbopol® UltrezTM 10, Carbopol® UltrezTM 30, methyl cellulose, and glycerin ointment. The hormone concentration was 1 mg/g of the hydrogel. We assessed the influence of model hydrogels on the pharmaceutical availability of insulin in vitro, and we examined the rheological and the texture parameters of the prepared formulations. Based on spectroscopic methods, we evaluated the influence of model hydrogels on secondary and tertiary structures of insulin. The analysis of rheograms showed that hydrogels are typical of shear-thinning non-Newtonian thixotropic fluids. Insulin release from the formulations occurs in a prolonged manner, providing a longer duration of action of the hormone. The stability of insulin in hydrogels was confirmed. The presence of model hydrogel carriers affects the secondary and the tertiary structures of insulin. The obtained results indicate that hydrogels are promising carriers in the treatment of diabetic foot ulcers. The most effective treatment can be achieved with a methyl cellulose-based insulin preparation. Full article
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18 pages, 4039 KiB  
Article
Development of a Biphasic-Release Multiple-Unit Pellet System with Diclofenac Sodium Using Novel Calcium Phosphate-Based Starter Pellets
by Daniel Zakowiecki, Maja Frankiewicz, Tobias Hess, Krzysztof Cal, Maciej Gajda, Justyna Dabrowska, Bartlomiej Kubiak, Jadwiga Paszkowska, Marcela Wiater, Dagmara Hoc, Grzegorz Garbacz and Dorota Haznar-Garbacz
Pharmaceutics 2021, 13(6), 805; https://doi.org/10.3390/pharmaceutics13060805 - 28 May 2021
Cited by 8 | Viewed by 6229
Abstract
Novel calcium phosphate-based starter pellets were used to develop a biphasic-release multiple-unit pellet system (MUPS) with diclofenac sodium as a model drug in the form of hard gelatin capsules. For comparative purposes, corresponding formulations based on the inert cores made of microcrystalline cellulose, [...] Read more.
Novel calcium phosphate-based starter pellets were used to develop a biphasic-release multiple-unit pellet system (MUPS) with diclofenac sodium as a model drug in the form of hard gelatin capsules. For comparative purposes, corresponding formulations based on the inert cores made of microcrystalline cellulose, sucrose and isomalt were prepared. The developed system consisted of two types of drug-layered pellets attaining different release patterns: delayed-release (enteric-coated) and extended-release. Dissolution characteristics were examined using both compendial and biorelevant methods, which reflected fed and fasting conditions. The results were collated with an equivalent commercial product but prepared with the direct pelletization technique. Full article
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19 pages, 2193 KiB  
Article
Development and Bio-Predictive Evaluation of Biopharmaceutical Properties of Sustained-Release Tablets with a Novel GPR40 Agonist for a First-in-Human Clinical Trial
by Ewelina Juszczyk, Kamil Kisło, Paweł Żero, Ewa Tratkiewicz, Maciej Wieczorek, Jadwiga Paszkowska, Grzegorz Banach, Marcela Wiater, Dagmara Hoc, Grzegorz Garbacz, Jaroslaw Sczodrok and Dorota Danielak
Pharmaceutics 2021, 13(6), 804; https://doi.org/10.3390/pharmaceutics13060804 - 28 May 2021
Cited by 4 | Viewed by 2810
Abstract
Sustained-release (SR) formulations may appear advantageous in first-in-human (FIH) study of innovative medicines. The newly developed SR matrix tablets require prolonged maintenance of API concentration in plasma and should be reliably assessed for the risk of uncontrolled release of the drug. In the [...] Read more.
Sustained-release (SR) formulations may appear advantageous in first-in-human (FIH) study of innovative medicines. The newly developed SR matrix tablets require prolonged maintenance of API concentration in plasma and should be reliably assessed for the risk of uncontrolled release of the drug. In the present study, we describe the development of a robust SR matrix tablet with a novel G-protein-coupled receptor 40 (GPR40) agonist for first-in-human studies and introduce a general workflow for the successful development of SR formulations for innovative APIs. The hydrophilic matrix tablets containing the labeled API dose of 5, 30, or 120 mg were evaluated with several methods: standard USP II dissolution, bio-predictive dissolution tests, and the texture and matrix formation analysis. The standard dissolution tests allowed preselection of the prototypes with the targeted dissolution rate, while the subsequent studies in physiologically relevant conditions revealed unwanted and potentially harmful effects, such as dose dumping under an increased mechanical agitation. The developed formulations were exceptionally robust toward the mechanical and physicochemical conditions of the bio-predictive tests and assured a comparable drug delivery rate regardless of the prandial state and dose labeled. In conclusion, the introduced development strategy, when implemented into the development cycle of SR formulations with innovative APIs, may allow not only to reduce the risk of formulation-related failure of phase I clinical trial but also effectively and timely provide safe and reliable medicines for patients in the trial and their further therapy. Full article
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20 pages, 2940 KiB  
Article
Buccal Resveratrol Delivery System as a Potential New Concept for the Periodontitis Treatment
by Magdalena Paczkowska-Walendowska, Jakub Dvořák, Natalia Rosiak, Ewa Tykarska, Emilia Szymańska, Katarzyna Winnicka, Marek A. Ruchała and Judyta Cielecka-Piontek
Pharmaceutics 2021, 13(3), 417; https://doi.org/10.3390/pharmaceutics13030417 - 20 Mar 2021
Cited by 16 | Viewed by 3495
Abstract
The health benefits of resveratrol have been proven to inhibit the development of numerous diseases. A frequent limitation in its use is a low bioavailability stemming from a poor solubility and fast enterohepatic metabolism. Thus, the aim of the research was to investigate [...] Read more.
The health benefits of resveratrol have been proven to inhibit the development of numerous diseases. A frequent limitation in its use is a low bioavailability stemming from a poor solubility and fast enterohepatic metabolism. Thus, the aim of the research was to investigate the possibility to formulate mucoadhesive cyclodextrin- and xanthan gum-based buccal tablets in order to increase the solubility of resveratrol and to eliminate bypass enterohepatic metabolism. Systems of resveratrol with α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) prepared by the dry mixing method (ratio 1:1) were selected for the of tablets where xanthan gum was used as a mucoadhesive agent. They were identified on the basis of PXRD, FT-IR analysis. Tablets F1 (with α-CD), F2 (with β-CD) and F3 (with γ-CD) were characterized by the highest compactibility as well as by favorable mucoadhesive properties. Resveratrol release from these tablets was delayed and controlled by diffusion. The tablets prepared in the course of this study appear to constitute promising resveratrol delivery systems and are recommended to increase the effectiveness of the treatment in many diseases, particularly periodontitis. Full article
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12 pages, 2610 KiB  
Article
Determination of Inherent Dissolution Performance of Drug Substances
by Dominik Sleziona, Amelie Mattusch, Gerhard Schaldach, David R. Ely, Gabriele Sadowski and Markus Thommes
Pharmaceutics 2021, 13(2), 146; https://doi.org/10.3390/pharmaceutics13020146 - 22 Jan 2021
Cited by 4 | Viewed by 2211
Abstract
The dissolution behavior of novel active pharmaceutical ingredients (API) is a crucial parameter in drug formulation since it frequently affects the drug release. Generally, a distinction is made between surface-reaction- and diffusion-controlled drug release. Therefore, dissolution studies such as the intrinsic dissolution test [...] Read more.
The dissolution behavior of novel active pharmaceutical ingredients (API) is a crucial parameter in drug formulation since it frequently affects the drug release. Generally, a distinction is made between surface-reaction- and diffusion-controlled drug release. Therefore, dissolution studies such as the intrinsic dissolution test defined in the pharmacopeia have been performed for many years. In order to overcome the disadvantages of the common intrinsic dissolution test, a new experimental setup was developed within this study. Specifically, a flow channel was designed and tested for measuring the mass transfer from a flat, solid surface dissolving into a fluid flowing over the surface with well-defined flow conditions. A mathematical model was developed that distinguishes between surface-reaction- and diffusion-limited drug release based on experimental data. Three different drugs—benzocaine, theophylline and griseofulvin—were used to investigate the mass flux during dissolution due to surface reaction, diffusion and convection kinetics. This new technique shows potential to be a valuable tool for the identification of formulation strategies. Full article
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20 pages, 4067 KiB  
Article
Physicochemical Characterization of a Co-Amorphous Atorvastatin-Irbesartan System with a Potential Application in Fixed-Dose Combination Therapy
by Marcin Skotnicki, Barbara Jadach, Agnieszka Skotnicka, Bartłomiej Milanowski, Lidia Tajber, Marek Pyda and Jacek Kujawski
Pharmaceutics 2021, 13(1), 118; https://doi.org/10.3390/pharmaceutics13010118 - 18 Jan 2021
Cited by 23 | Viewed by 3577
Abstract
The aim of this study was to characterize a 1:1 molar ratio of a pharmacologically relevant co-amorphous atorvastatin-irbesartan (ATR-IRB) system obtained by quench cooling of the crystalline ATR/IRB physical mixture for potential use in the fixed-dose combination therapy. The system was characterized by [...] Read more.
The aim of this study was to characterize a 1:1 molar ratio of a pharmacologically relevant co-amorphous atorvastatin-irbesartan (ATR-IRB) system obtained by quench cooling of the crystalline ATR/IRB physical mixture for potential use in the fixed-dose combination therapy. The system was characterized by employing standard differential scanning calorimetry (DSC), Fourier transform-infrared spectroscopy (FT-IR), and intrinsic dissolution rate studies. Quantum mechanical calculations were performed to obtain information regarding intermolecular interactions in the studied co-amorphous ATR-IRB system. The co-amorphous formulation showed a significant improvement in the intrinsic dissolution rate (IDR) of IRB over pure crystalline as well as its amorphous counterpart. An unusual behavior was observed for ATR, as the IDR of ATR in the co-amorphous formulation was slightly lower than that of amorphous ATR alone. Short-term physical aging studies of up to 8 h proved that the ATR-IRB co-amorphous system remained in the amorphous form. Furthermore, no physical aging occurred in the co-amorphous system. FT-IR, density functional theory calculations, and analysis of Tg value of co-amorphous system using the Couchman–Karasz equation revealed the presence of molecular interactions between APIs, which may contribute to the increased physical stability. Full article
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Review

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18 pages, 1562 KiB  
Review
Citric Acid: A Multifunctional Pharmaceutical Excipient
by Maria Lambros, Thac (Henry) Tran, Qinqin Fei and Mike Nicolaou
Pharmaceutics 2022, 14(5), 972; https://doi.org/10.3390/pharmaceutics14050972 - 30 Apr 2022
Cited by 27 | Viewed by 11944
Abstract
Citric acid, a tricarboxylic acid, has found wide application in the chemical and pharmaceutical industry due to its biocompatibility, versatility, and green, environmentally friendly chemistry. This review emphasizes the pharmaceutical uses of citric acid as a strategic ingredient in drug formulation while focusing [...] Read more.
Citric acid, a tricarboxylic acid, has found wide application in the chemical and pharmaceutical industry due to its biocompatibility, versatility, and green, environmentally friendly chemistry. This review emphasizes the pharmaceutical uses of citric acid as a strategic ingredient in drug formulation while focusing on the impact of its physicochemical properties. The functionality of citric acid is due to its three carboxylic groups and one hydroxyl group. These allow it to be used in many ways, including its ability to be used as a crosslinker to form biodegradable polymers and as a co-former in co-amorphous and co-crystal applications. This paper also analyzes the effect of citric acid in physiological processes and how this effect can be used to enhance the attributes of pharmaceutical preparations, as well as providing a critical discussion on the issues that may arise out of the presence of citric acid in formulations. Full article
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