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

Deadline for manuscript submissions: closed (20 September 2020) | Viewed by 43427

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Dr. Roberta Censi

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School of Pharmacy, Drug Delivery Division, University of Camerino, CHIP Research, Camerino, Italy
Interests: pharmaceutical technology; formulation; biomaterials; hydrogels; nanoparticles; polymorphism
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Piera Di Martino

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Department of Pharmacy, University G. D’Annunzio Chieti-Pescara, 66100 Chieti, Italy
Interests: nanomedicines; hydrogels; nanoparticles; nanohydrogels; drug delivery systems
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are pleased to announce the new Special Issue for Pharmaceutics entitled “Drug Polymorphism and Dosage Form Design”.

Extensive academic and industrial research demonstrated that more than 50% of the currently used APIs shows multiple physical arrangement of the constituents in the crystal lattice. This polymorphism significantly influences a variety of drug properties, including dissolution rate, solubility, tabletability, flowability, stability and even bioavailability, efficacy and toxicity. Pioneered by Aguiar et al in the ‘60s, surprisingly, after many decades, this research area is still attracting much attention by the scientific community and motivated the edition of this Special Issue, that is aimed at gathering the most recent advances in the field of polymorphism, highlighting its relevance in the Pharmaceutical Sciences and in the Design of Dosage Forms.

Original research articles and review articles dealing with all the aspects of drug polymorphism are considered. Particularly, the discovery of new crystal forms, methods for their preparation, influence of the polymorphism on the physicochemical properties, analytical methods for the study of crystal forms, API stability during processing and storage, biological effects of polymorphism, preformulation studies, design of dosage forms and regulatory implications are all included in this Special Issue.

Dr. Roberta Censi
Prof. Dr. Piera Di Martino
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. 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

Amorphism
Dissolution
Polymorphism
Dosage form
Bioavailability
Stability
Mechanical properties
Tabletability
Flowability
Analytical methods

Related Special Issue

Drug Polymorphism and Dosage Form Design, 2nd Edition in Pharmaceutics

Published Papers (10 papers)

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Research

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18 pages, 3786 KiB

Open AccessArticle

Molecular Crystal Forms of Antitubercular Ethionamide with Dicarboxylic Acids: Solid-State Properties and a Combined Structural and Spectroscopic Study

by Simone Bordignon, Paolo Cerreia Vioglio, Elena Amadio, Federica Rossi, Emanuele Priola, Dario Voinovich, Roberto Gobetto and Michele R. Chierotti

Pharmaceutics 2020, 12(9), 818; https://doi.org/10.3390/pharmaceutics12090818 - 28 Aug 2020

Cited by 6 | Viewed by 2595

Abstract

We report on the preparation, characterization, and bioavailability properties of three new crystal forms of ethionamide, an antitubercular agent used in the treatment of drug-resistant tuberculosis. The new adducts were obtained by combining the active pharmaceutical ingredient with three dicarboxylic acids, namely glutaric, malonic and tartaric acid, in equimolar ratios. Crystal structures were obtained for all three adducts and were compared with two previously reported multicomponent systems of ethionamide with maleic and fumaric acid. The ethionamide-glutaric acid and the ethionamide-malonic acid adducts were thoroughly characterized by means of solid-state NMR (¹³C and ¹⁵N Cross-Polarization Magic Angle Spinning or CPMAS) to confirm the position of the carboxylic proton, and they were found to be a cocrystal and a salt, respectively; they were compared with two previously reported multicomponent systems of ethionamide with maleic and fumaric acid. Ethionamide-tartaric acid was found to be a rare example of kryptoracemic cocrystal. In vitro bioavailability enhancements up to a factor 3 compared to pure ethionamide were assessed for all obtained adducts. Full article

(This article belongs to the Special Issue Drug Polymorphism and Dosage Form Design)

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15 pages, 2509 KiB

Open AccessArticle

Physical Ageing of Amorphous Indapamide Characterised by Differential Scanning Calorimetry

by Agata Drogoń, Marcin Skotnicki, Agnieszka Skotnicka and Marek Pyda

Pharmaceutics 2020, 12(9), 800; https://doi.org/10.3390/pharmaceutics12090800 - 25 Aug 2020

Cited by 8 | Viewed by 2856

Abstract

The objective of this study was to characterise amorphous indapamide (IND) subjected to the physical ageing process by differential scanning calorimetry (DSC). The amorphous indapamide was annealed at different temperatures below the glass transition, i.e., 35, 40, 45, 65, 75 and 85 °C for different lengths of time, from 30 min up to a maximum of 32 h. DSC was used to characterise both the crystalline and the freshly prepared glass and to monitor the extent of relaxation at temperatures below the glass transition (T_g). No ageing occurred at 35, 40 and 45 °C at the measured lengths of times. Molecular relaxation time constants (τ^KWW) for samples aged at 65, 75 and 85 °C were determined by the Kohlrausch-Williams-Watts (KWW) equation. The fragility parameter m (a measure of the stability below the glass transition) was determined from the T_g dependence from the cooling and heating rates, and IND was found to be relatively stable (“moderately fragile”) in the amorphous state. Temperature-modulated DSC was used to separate reversing and nonreversing processes for unaged amorphous IND. The enthalpy relaxation peak was clearly observed as a part of the nonreversing signal. Heat capacities data for unaged and physically aged IND were fitted to C_p baselines of solid and liquid states of IND, were integrated and enthalpy was presented as a function of temperature. Full article

(This article belongs to the Special Issue Drug Polymorphism and Dosage Form Design)

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21 pages, 5293 KiB

Open AccessArticle

Compression-Induced Phase Transitions of Bicalutamide

by Joanna Szafraniec-Szczęsny, Agata Antosik-Rogóż, Justyna Knapik-Kowalczuk, Mateusz Kurek, Ewa Szefer, Karolina Gawlak, Krzysztof Chmiel, Sebastian Peralta, Krzysztof Niwiński, Krzysztof Pielichowski, Marian Paluch and Renata Jachowicz

Pharmaceutics 2020, 12(5), 438; https://doi.org/10.3390/pharmaceutics12050438 - 09 May 2020

Cited by 13 | Viewed by 3841

Abstract

The formation of solid dispersions with the amorphous drug dispersed in the polymeric matrix improves the dissolution characteristics of poorly soluble drugs. Although they provide an improved absorption after oral administration, the recrystallization, which can occur upon absorption of moisture or during solidification and other formulation stages, serves as a major challenge. This work aims at understanding the amorphization-recrystallization changes of bicalutamide. Amorphous solid dispersions with poly(vinylpyrrolidone-co-vinyl acetate) (PVP/VA) were obtained by either ball milling or spray drying. The applied processes led to drug amorphization as confirmed using X-ray diffraction and differential scanning calorimetry. Due to a high propensity towards mechanical activation, the changes of the crystal structure of physical blends of active pharmaceutical ingredient (API) and polymer upon pressure were also examined. The compression led to drug amorphization or transition from form I to form II polymorph, depending on the composition and applied force. The formation of hydrogen bonds confirmed using infrared spectroscopy and high miscibility of drug and polymer determined using non-isothermal dielectric measurements contributed to the high stability of amorphous solid dispersions. They exhibited improved wettability and dissolution enhanced by 2.5- to 11-fold in comparison with the crystalline drug. The drug remained amorphous upon compression when the content of PVP/VA in solid dispersions exceeded 20% or 33%, in the case of spray-dried and milled systems, respectively. Full article

(This article belongs to the Special Issue Drug Polymorphism and Dosage Form Design)

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21 pages, 3784 KiB

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Co-crystals, Salts or Mixtures of Both? The Case of Tenofovir Alafenamide Fumarates

by Hannes Lengauer, Damjan Makuc, Damjan Šterk, Franc Perdih, Arthur Pichler, Tina Trdan Lušin, Janez Plavec and Zdenko Časar

Pharmaceutics 2020, 12(4), 342; https://doi.org/10.3390/pharmaceutics12040342 - 10 Apr 2020

Cited by 9 | Viewed by 5222

Abstract

Tenofovir alafenamide fumarate (TAF) is the newest prodrug of tenofovir that constitutes several drug products used for the treatment of HIV/AIDS. Although the solid-state properties of its predecessor tenofovir disoproxil fumarate have been investigated and described in the literature, there are no data in the scientific literature on the solid state properties of TAF. In our report, we describe the preparation of two novel polymorphs II and III of tenofovir alafenamide monofumarate (TA MF2 and TA MF3). The solid-state structure of these compounds was investigated in parallel to the previously known tenofovir alafenamide monofumarate form I (TA MF1) and tenofovir alafenamide hemifumarate (TA HF). Interestingly, the single-crystal X-ray diffraction of TA HF revealed that this derivative exists as a co-crystal form. In addition, we prepared a crystalline tenofovir alafenamide free base (TA) and its hydrochloride salt (TA HCl), which enabled us to determine the structure of TA MF derivatives using ¹⁵N-ssNMR (¹⁵N-solid state nuclear magnetic resonance). Surprisingly, we observed that TA MF1 exists as a mixed ionization state complex or pure salt, while TA MF2 and TA MF3 can be obtained as pure co-crystal forms. Full article

(This article belongs to the Special Issue Drug Polymorphism and Dosage Form Design)

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22 pages, 4257 KiB

Open AccessArticle

Mechanochemical Formation of Racemic Praziquantel Hemihydrate with Improved Biopharmaceutical Properties

by Debora Zanolla, Dritan Hasa, Mihails Arhangelskis, Gabriela Schneider-Rauber, Michele R. Chierotti, Jennifer Keiser, Dario Voinovich, William Jones and Beatrice Perissutti

Pharmaceutics 2020, 12(3), 289; https://doi.org/10.3390/pharmaceutics12030289 - 23 Mar 2020

Cited by 20 | Viewed by 4666

Abstract

Praziquantel (PZQ) is the first-line drug used against schistosomiasis, one of the most common parasitic diseases in the world. A series of crystalline structures including two new polymorphs of the pure drug and a series of cocrystals of PZQ have been discovered and deposited in the Cambridge Structural Database (CSD). This work adds to the list of multicomponent forms of PZQ a relevant example of a racemic hemihydrate (PZQ-HH), obtainable from commercial PZQ (polymorphic Form A) through mechanochemistry. Noteworthy, the formation of the new hemihydrate strongly depends on the initial polymorphic form of PZQ and on the experimental conditions used. The new PZQ-HH has been fully characterized by means of HPLC, Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Hot-Stage Microscopy (SEM), Powder X-Ray Diffraction (PXRD), Scanning Electron Microscopy (SEM), FT-IR, polarimetry, solid-state NMR (SS-NMR), solubility and intrinsic dissolution rate (IDR), and in vitro tests on Schistosoma mansoni adults. The crystal structure was solved from the powder X-ray diffraction pattern and validated by periodic-DFT calculations. The new bioactive hemihydrate was physically stable for three months and showed peculiar biopharmaceutical features including enhanced solubility and a double intrinsic dissolution rate in water in comparison to the commercially available PZQ Form A. Full article

(This article belongs to the Special Issue Drug Polymorphism and Dosage Form Design)

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18 pages, 8340 KiB

Open AccessArticle

Stabilisation and Growth of Metastable Form II of Fluconazole in Amorphous Solid Dispersions

by Maciej Nowak, Maciej Gajda, Przemysław Baranowski, Patrycja Szymczyk, Bożena Karolewicz and Karol P. Nartowski

Pharmaceutics 2020, 12(1), 12; https://doi.org/10.3390/pharmaceutics12010012 - 20 Dec 2019

Cited by 12 | Viewed by 4026

Abstract

The crystallisation of metastable drug polymorphs in polymer matrices has been reported as a successful approach to enhance the solubility of poorly water-soluble drug molecules. This can be achieved using different polymers, drug to polymer ratios and formulation techniques enabling the formation of stable nuclei and subsequent growth of new or metastable drug polymorphs. In this work we elucidated the polymorphism behaviour of a model compound fluconazole (FLU) embedded in solid dispersions with amorphous Soluplus^® (SOL) obtained using spray drying and fusion methods. The effect of humidity on the stability of FLU in the obtained dispersions was also evaluated. FLU at a drug content below 40 wt. % stayed amorphous in the dispersions prepared using the fusion method and crystallised exclusively into metastable form II at a drug content above 40 wt. % and 70% relative humidity (RH) conditions. In contrast, a mixture of forms I, II and hydrate of FLU was detected in the spray dried formulations after 14 days of storage at 40 °C/40% RH, with preferential growth of thermodynamically stable form I of FLU. This study highlights the importance of preparation techniques and the drug:polymer ratio in the formulation of amorphous solid dispersions and provides further understanding of the complex crystallisation behaviour of amorphous pharmaceuticals encapsulated in the polymer matrixes. Full article

(This article belongs to the Special Issue Drug Polymorphism and Dosage Form Design)

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Review

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19 pages, 2801 KiB

Open AccessReview

Combining Surface Templating and Confinement for Controlling Pharmaceutical Crystallization

by Manali Banerjee and Blair Brettmann

Pharmaceutics 2020, 12(10), 995; https://doi.org/10.3390/pharmaceutics12100995 - 20 Oct 2020

Cited by 15 | Viewed by 4282

Abstract

Poor water solubility is one of the major challenges to the development of oral dosage forms containing active pharmaceutical ingredients (APIs). Polymorphism in APIs leads to crystals with different surface wettabilities and free energies, which can lead to different dissolution properties. Crystal size and habit further contribute to this variability. An important focus in pharmaceutical research has been on controlling the drug form to improve the solubility and thus bioavailability of APIs. In this regard, heterogeneous crystallization on surfaces and crystallization under confinement have become prominent forms of controlling polymorphism and drug crystal size and habits; however there has not been a thorough review into the emerging field of combining these approaches to control crystallization. This tutorial-style review addresses the major advances that have been made in controlling API forms using combined crystallization methods. By designing templates that not only control the surface functionality but also enable confinement of particles within a porous structure, these combined systems have the potential to provide better control over drug polymorph formation and crystal size and habit. This review further provides a perspective on the future of using a combined crystallization approach and suggests that combining surface templating with confinement provides the advantage of both techniques to rationally design systems for API nucleation. Full article

(This article belongs to the Special Issue Drug Polymorphism and Dosage Form Design)

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25 pages, 2007 KiB

Open AccessReview

Pharmaceutical Hydrates Analysis—Overview of Methods and Recent Advances

by Ewa Jurczak, Anna Helena Mazurek, Łukasz Szeleszczuk, Dariusz Maciej Pisklak and Monika Zielińska-Pisklak

Pharmaceutics 2020, 12(10), 959; https://doi.org/10.3390/pharmaceutics12100959 - 11 Oct 2020

Cited by 52 | Viewed by 5768

Abstract

This review discusses a set of instrumental and computational methods that are used to characterize hydrated forms of APIs (active pharmaceutical ingredients). The focus has been put on highlighting advantages as well as on presenting some limitations of the selected analytical approaches. This has been performed in order to facilitate the choice of an appropriate method depending on the type of the structural feature that is to be analyzed, that is, degree of hydration, crystal structure and dynamics, and (de)hydration kinetics. The presented techniques include X-ray diffraction (single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD)), spectroscopic (solid state nuclear magnetic resonance spectroscopy (ssNMR), Fourier-transformed infrared spectroscopy (FT-IR), Raman spectroscopy), thermal (differential scanning calorimetry (DSC), thermogravimetric analysis (TGA)), gravimetric (dynamic vapour sorption (DVS)), and computational (molecular mechanics (MM), Quantum Mechanics (QM), molecular dynamics (MD)) methods. Further, the successful applications of the presented methods in the studies of hydrated APIs as well as studies on the excipients’ influence on these processes have been described in many examples. Full article

(This article belongs to the Special Issue Drug Polymorphism and Dosage Form Design)

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12 pages, 908 KiB

Open AccessReview

Molecular Interactions in Solid Dispersions of Poorly Water-Soluble Drugs

by Thao T. D. Tran and Phuong H. L. Tran

Pharmaceutics 2020, 12(8), 745; https://doi.org/10.3390/pharmaceutics12080745 - 07 Aug 2020

Cited by 31 | Viewed by 3625

Abstract

Physicochemical characterization is a crucial step for the successful development of solid dispersions, including the determination of drug crystallinity and molecular interactions. Typically, the detection of molecular interactions will assist in the explanation of different drug performances (e.g., dissolution, solubility, stability) in solid dispersions. Various prominent reviews on solid dispersions have been reported recently. However, there is still no overview of recent techniques for evaluating the molecular interactions that occur within solid dispersions of poorly water-soluble drugs. In this review, we aim to overview common methods that have been used for solid dispersions to identify different bond formations and forces via the determination of interaction energy. In addition, a brief background on the important role of molecular interactions will also be described. The summary and discussion of methods used in the determination of molecular interactions will contribute to further developments in solid dispersions, especially for quick and potent drug delivery applications. Full article

(This article belongs to the Special Issue Drug Polymorphism and Dosage Form Design)

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9 pages, 435 KiB

Open AccessReview

The Polymorphism of Drugs: New Approaches to the Synthesis of Nanostructured Polymorphs

by Dmitry Chistyakov and Gleb Sergeev

Pharmaceutics 2020, 12(1), 34; https://doi.org/10.3390/pharmaceutics12010034 - 01 Jan 2020

Cited by 37 | Viewed by 5083

Abstract

Among the significant problems of modern pharmacology are the low solubility and bioavailability of drugs. One way to resolve this problem is to obtain new polymorphic forms of drugs with improved physicochemical properties. Various approaches have been developed with this aim, including the preparation of co-crystals, the use of nanoparticles, or the use of compounds in the form of a salt. A promising direction in pharmacology concerns the production of new stable polymorphic structures. In this mini-review, we consider certain aspects of drug polymorphism, methods for the synthesis of polymorphs, and the stability, size, and transformation of crystalline polymorphs. Moreover, we summarize our results from several studies demonstrating the problems associated with the synthesis of new polymorphous modifications based on inert gases and cryotemperatures. The results indicate that the problems specific to drug polymorphisms have only been partly resolved, are of current interest, and require further development. Full article

(This article belongs to the Special Issue Drug Polymorphism and Dosage Form Design)

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