Applications of Crystal Engineering in Drug Delivery

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

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 30788

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The School of Pharmacy, University of Reading, Reading RG6 6AD, UK
Interests: amorphous polymeric solid dispersions; pulmonary drug delivery; oral drug delivery; co-crystals; co-amorphous dispersions
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Special Issue Information

Dear Colleagues,

Manuscripts are invited for publication in a Special Issue of Pharmaceutics entitled "Applications of Crystal Engineering in Drug Delivery". This Special Issue is focused on the use of crystal engineering methods to improve drug properties such as solubility and dissolution rate for optimum drug delivery.  Crystal engineering is a broad area of research that included crystal habit modification, polymorphism, solid dispersions, and salt formation.  All these pre-formulation and formulation techniques entail that the drug can be modified using methods such as solvent evaporation or dry methods such as mechanochemical activation.  Often, the drug properties can be significantly altered when the crystalline structure is altered or even completely vanish, such as in the case of amorphous form formation.  The outcome of such modifications affects physical properties and can have a dramatic impact on physiological properties, such as bioavailability and absorption.  Drug delivery applications include various routes, such as oral, pulmonary, ophthalmic, buccal, vaginal, transdermal, and parenteral drug delivery. Recent advances in this area of research have shown potential application of these techniques to use crystal engineering to achieve targeted drug delivery for novel molecules such as anticancer drugs, antimicrobials, and vaccines. 

Dr. Hisham Al-Obaidi
Guest Editor

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Keywords

Manuscripts are invited for publication in a Special Issue of Pharmaceutics entitled "Applications of Crystal Engineering in Drug Delivery". This SI is focused on the use of crystal engineering methods to improve drug properties such as solubility and dissolution rate for optimum drug delivery.  Crystal engineering is a broad area of research that included crystal habit modification, polymorphism, solid dispersions, and salt formation.  All these pre-formulation and formulation techniques entail that the drug can be modified using methods such as solvent evaporation or dry methods such as mechanochemical activation.  

Drug delivery applications include various routes, such as oral, pulmonary, ophthalmic, buccal, vaginal, transdermal, and parenteral drug delivery. Recent advances in this area of research have shown potential application of these techniques to use crystal engineering to achieve targeted drug delivery for novel molecules such as anticancer drugs, antimicrobials, and vaccines.

  • crystal engineering
  • polymorphism
  • solvates
  • solid dispersions
  • poorly-soluble drugs
  • amorphous
  • crystallinity
  • polymer-drug mixtures
  • solid dosage forms
  • dissolution rate

Published Papers (13 papers)

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Research

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16 pages, 12976 KiB  
Article
Metformin-NSAIDs Molecular Salts: A Path towards Enhanced Oral Bioavailability and Stability
by Francisco Javier Acebedo-Martínez, Alicia Domínguez-Martín, Carolina Alarcón-Payer, Carolina Garcés-Bastida, Cristóbal Verdugo-Escamilla, Jaime Gómez-Morales and Duane Choquesillo-Lazarte
Pharmaceutics 2023, 15(2), 449; https://doi.org/10.3390/pharmaceutics15020449 - 29 Jan 2023
Cited by 4 | Viewed by 1863
Abstract
According to the World Health Organization, more than 422 million people worldwide have diabetes. The most common oral treatment for type 2 diabetes is the drug metformin (MTF), which is usually formulated as a hydrochloride to achieve higher water solubility. However, this drug [...] Read more.
According to the World Health Organization, more than 422 million people worldwide have diabetes. The most common oral treatment for type 2 diabetes is the drug metformin (MTF), which is usually formulated as a hydrochloride to achieve higher water solubility. However, this drug is also highly hygroscopic, thus showing stability problems. Another kind of worldwide prescribed drug is the non-steroidal anti-inflammatory drug (NSAID). These latter, on the contrary, show a low solubility profile; therefore, they must be administered at high doses, which increases the probability of secondary effects. In this work, novel drug-drug pharmaceutical solids combining MTF-NSAIDs have been synthesized in solution or by mechanochemical methods. The aim of this concomitant treatment is to improve the physicochemical properties of the parent active pharmaceutical ingredients. After a careful solid-state characterization along with solubility and stability studies, it can be concluded that the new molecular salt formulations enhance not only the stability of MTF but also the solubility of NSAIDs, thus giving promising results regarding the development of these novel pharmaceutical multicomponent solids. Full article
(This article belongs to the Special Issue Applications of Crystal Engineering in Drug Delivery)
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26 pages, 12333 KiB  
Article
The Formulation of Curcumin: 2-Hydroxypropyl-β-cyclodextrin Complex with Smart Hydrogel for Prolonged Release of Curcumin
by Ljubiša Nikolić, Maja Urošević, Vesna Nikolić, Ivana Gajić, Ana Dinić, Vojkan Miljković, Srđan Rakić, Sanja Đokić, Jelena Kesić, Snežana Ilić-Stojanović and Goran Nikolić
Pharmaceutics 2023, 15(2), 382; https://doi.org/10.3390/pharmaceutics15020382 - 22 Jan 2023
Cited by 5 | Viewed by 1916
Abstract
Curcumin comes from the plant species Curcuma longa and shows numerous pharmacological activities. There are numerous curcumin formulations with gels or cyclodextrins in order to increase its solubility and bioavailability. This paper presents the formulation of complex of curcumin with 2-hydroxypropyl-β-cyclodextrin in a [...] Read more.
Curcumin comes from the plant species Curcuma longa and shows numerous pharmacological activities. There are numerous curcumin formulations with gels or cyclodextrins in order to increase its solubility and bioavailability. This paper presents the formulation of complex of curcumin with 2-hydroxypropyl-β-cyclodextrin in a thermosensitive hydrogel, based on N-isopropylmethacrylamide and N-isopropylacrylamide with ethylene glycol dimethacrylate as a crosslinker. The product was characterized by chemical methods and also by FTIR, HPLC, DSC, SEM, XRD. The results show that synthesis was successfully done. With an increase in the quantity of crosslinker in the hydrogels, the starting release and the release rate of curcumin from the formulation of the complex with hydrogels decreases. The release rate of curcumin from the gel complex formulation is constant over time. It is possible to design a formulation that will release curcumin for more than 60 days. In order to determine the mechanism and kinetics of curcumin release, various mathematical models were applied by using the DDSolver package for Microsoft Excel application. The Korsmeyer-Peppas model best describes the release of curcumin from the gel formulation of the complex, while the values for the diffusion exponent (0.063–0.074) shows that mechanism of the release rate is based on diffusion. Full article
(This article belongs to the Special Issue Applications of Crystal Engineering in Drug Delivery)
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18 pages, 7961 KiB  
Article
The Solubility Studies and the Complexation Mechanism Investigations of Biologically Active Spiro[cyclopropane-1,3′-oxindoles] with β-Cyclodextrins
by Anna A. Kravtsova, Anna A. Skuredina, Alexander S. Malyshev, Irina M. Le-Deygen, Elena V. Kudryashova and Ekaterina M. Budynina
Pharmaceutics 2023, 15(1), 228; https://doi.org/10.3390/pharmaceutics15010228 - 9 Jan 2023
Cited by 3 | Viewed by 2180
Abstract
In this work, we first improved the aqueous solubility of biologically active spiro[cyclopropane-1,3′-oxindoles] (SCOs) via their complexation with different β-cyclodextrins (β-CDs) and proposed a possible mechanism of the complex formation. β-CDs significantly increased the water solubility of SCOs (up to fourfold). Moreover, the [...] Read more.
In this work, we first improved the aqueous solubility of biologically active spiro[cyclopropane-1,3′-oxindoles] (SCOs) via their complexation with different β-cyclodextrins (β-CDs) and proposed a possible mechanism of the complex formation. β-CDs significantly increased the water solubility of SCOs (up to fourfold). Moreover, the nature of the substituents in the β-CDs influenced the solubility of the guest molecule (MβCD > SBEβCD > HPβCD). Complexation preferably occurred via the inclusion of aromatic moieties of SCOs into the hydrophobic cavity of β-CDs by the numerous van der Waals contacts and formed stable supramolecular systems. The phase solubility technique and optical microscopy were used to determine the dissociation constants of the complexes (Kc~102 M−1) and reveal a significant decrease in the size of the formed crystals. FTIR-ATR microscopy, PXRD, and 1H-1H ROESY NMR measurements, as well as molecular modeling studies, were carried out to elucidate the host–guest interaction mechanism of the complexation. Additionally, in vitro experiments were carried out and revealed enhancements in the antibacterial activity of SCOs due to their complexation with β-CDs. Full article
(This article belongs to the Special Issue Applications of Crystal Engineering in Drug Delivery)
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19 pages, 3134 KiB  
Article
In Situ Co-Amorphization of Olanzapine in the Matrix and on the Coat of Pellets
by Nuno F. da Costa, Raquel F. Azevedo, João A. Lopes, Ana I. Fernandes and João F. Pinto
Pharmaceutics 2022, 14(12), 2587; https://doi.org/10.3390/pharmaceutics14122587 - 24 Nov 2022
Viewed by 1601
Abstract
In situ amorphization is a promising approach, considered in the present work, to enhance the solubility and dissolution rate of olanzapine, while minimizing the exposure of the amorphous material to the stress conditions applied during conventional processing. The production of pellets by extrusion/spheronization [...] Read more.
In situ amorphization is a promising approach, considered in the present work, to enhance the solubility and dissolution rate of olanzapine, while minimizing the exposure of the amorphous material to the stress conditions applied during conventional processing. The production of pellets by extrusion/spheronization and the coating of inert beads were investigated as novel methods to promote the co-amorphization of olanzapine, a poorly water-soluble drug, and saccharin. Samples were characterized using differential scanning calorimetry, X-ray powder diffraction, Fourier-transform infrared spectroscopy and scanning electron microscopy, and dissolution and stability testing. The co-amorphous produced were compared with crystalline olanzapine, or physical mixture of olanzapine and saccharin. Results suggested that the addition of water to mixtures containing olanzapine and saccharin during the production of pellets, and the coating of inert beads, induced the in situ co-amorphization of these substances. The coating of inert beads enhanced the solubility and dissolution rate of olanzapine, especially when compared to pellets coated with the crystalline drug, but also with pellets containing the co-amorphous entity in the matrix of beads. Nine months stability tests (23 °C/60% RH) confirmed the preservation of the solid-state properties of the co-amorphous form on/in pellets. Overall, results highlighted the feasibility and benefits of in situ co-amorphization, either when the drug was entrapped in the pellets matrix, or preferentially applied directly on the surface of pellets. Full article
(This article belongs to the Special Issue Applications of Crystal Engineering in Drug Delivery)
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18 pages, 6478 KiB  
Article
Crystal Engineering of Ionic Cocrystals Sustained by Azolium···Azole Heterosynthons
by Maryam Rahmani, Vijith Kumar, Julia Bruno-Colmenarez and Michael J. Zaworotko
Pharmaceutics 2022, 14(11), 2321; https://doi.org/10.3390/pharmaceutics14112321 - 28 Oct 2022
Cited by 2 | Viewed by 1632
Abstract
Crystal engineering of multi-component molecular crystals, cocrystals, is a subject of growing interest, thanks in part to the potential utility of pharmaceutical cocrystals as drug substances with improved properties. Whereas molecular cocrystals (MCCs) are quite well studied from a design perspective, ionic cocrystals [...] Read more.
Crystal engineering of multi-component molecular crystals, cocrystals, is a subject of growing interest, thanks in part to the potential utility of pharmaceutical cocrystals as drug substances with improved properties. Whereas molecular cocrystals (MCCs) are quite well studied from a design perspective, ionic cocrystals (ICCs) remain relatively underexplored despite there being several recently FDA-approved drug products based upon ICCs. Successful cocrystal design strategies typically depend on strong and directional noncovalent interactions between coformers, as exemplified by hydrogen bonds. Understanding of the hierarchy of such interactions is key to successful outcomes in cocrystal design. We herein address the crystal engineering of ICCs comprising azole functional groups, particularly imidazoles and triazoles, which are commonly encountered in biologically active molecules. Specifically, azoles were studied for their propensity to serve as coformers with strong organic (trifluoroacetic acid and p-toluenesulfonic acid) and inorganic (hydrochloric acid, hydrobromic acid and nitric acid) acids to gain insight into the hierarchy of NH+···N (azolium-azole) supramolecular heterosynthons. Accordingly, we combined data mining of the Cambridge Structural Database (CSD) with the structural characterization of 16 new ICCs (11 imidazoles, 4 triazoles, one imidazole-triazole). Analysis of the new ICCs and 66 relevant hits archived in the CSD revealed that supramolecular synthons between identical azole rings (A+BA) are much more commonly encountered, 71, than supramolecular synthons between different azole rings (A+BC), 11. The average NH+···N distance found in the new ICCs reported herein is 2.697(3) Å and binding energy calculations suggested that hydrogen bond strengths range from 31–46 kJ mol−1. The azolium-triazole ICC (A+BC) was obtained via mechanochemistry and differed from the other ICCs studied as there was no NH+···N hydrogen bonding. That the CNC angles in imidazoles and 1,2,4-triazoles are sensitive to protonation, the cationic forms having larger (approximately 4.4 degrees) values than comparable neutral rings, was used as a parameter to distinguish between protonated and neutral azole rings. Our results indicate that ICCs based upon azolium-azole supramolecular heterosynthons are viable targets, which has implications for the development of new azole drug substances with improved properties. Full article
(This article belongs to the Special Issue Applications of Crystal Engineering in Drug Delivery)
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18 pages, 3990 KiB  
Article
Insight into the Formation of Cocrystal and Salt of Tenoxicam from the Isomer and Conformation
by Yifei Xie, Penghui Yuan, Tianyu Heng, Lida Du, Qi An, Baoxi Zhang, Li Zhang, Dezhi Yang, Guanhua Du and Yang Lu
Pharmaceutics 2022, 14(9), 1968; https://doi.org/10.3390/pharmaceutics14091968 - 19 Sep 2022
Cited by 9 | Viewed by 1927
Abstract
Tenoxicam (TNX) is a new non-steroidal anti-inflammatory drug that shows a superior anti-inflammatory effect and has the advantages of a long half-life period, a fast onset of action, a small dose, complete metabolism, and good tolerance. Some compounds often have tautomerism, and different [...] Read more.
Tenoxicam (TNX) is a new non-steroidal anti-inflammatory drug that shows a superior anti-inflammatory effect and has the advantages of a long half-life period, a fast onset of action, a small dose, complete metabolism, and good tolerance. Some compounds often have tautomerism, and different tautomers exist in different crystalline forms. TNX is such a compound and has three tautomers. TNX always exists as the zwitterionic form in cocrystals. When the salt is formed, TNX exists in the enol form, which exhibits two conformations depending on whether a proton is gained or lost. Currently, the crystal structure of the keto form is not in the Cambridge Structural Database (CSD). Based on the analysis of existing crystal structures, we derived a simple rule for what form of TNX exists according to the pKa value of the cocrystal coformer (CCF) and carried out validation tests using three CCFs with different pKa values, including p-aminosalicylic acid (PAS), 3,5-dinitrobenzoic acid (DNB), and 2,6-dihydroxybenzoic acid (DHB). The molecular surface electrostatic potential (MEPS) was combined with the pKa rule to predict the interaction sites. Finally, two new cocrystals (TNX-PAS and TNX-DNB) and one salt (TNX-DHB) of TNX were obtained as expected. The differences between the cocrystals and salt were distinguished by X-ray diffraction, vibration spectra, thermal analysis, and dissolution measurements. To further understand the intermolecular interactions in these cocrystals and salt, the lattice energy and energy decomposition analysis (EDA) were used to explain them from the perspective of energy. The results suggest that the melting point of the CCF determines that of the cocrystal or salt, the solubility of the CCF itself plays an important role, and the improvement of the solubility after salt formation is not necessarily better than that of API or its cocrystals. Full article
(This article belongs to the Special Issue Applications of Crystal Engineering in Drug Delivery)
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19 pages, 4318 KiB  
Article
Varied Bulk Powder Properties of Micro-Sized API within Size Specifications as a Result of Particle Engineering Methods
by Zijian Wang, Marina Solomos, Stephanus Axnanda, Chienhung Chen, Margaret Figus, Luke Schenck and Changquan Calvin Sun
Pharmaceutics 2022, 14(9), 1901; https://doi.org/10.3390/pharmaceutics14091901 - 8 Sep 2022
Cited by 5 | Viewed by 3038
Abstract
Micronized particles are commonly used to improve the content uniformity (CU), dissolution performance, and bioavailability of active pharmaceutical ingredients (API). Different particle engineering routes have been developed to prepare micron-sized API in a specific size range to deliver desirable biopharmaceutical performance. However, such [...] Read more.
Micronized particles are commonly used to improve the content uniformity (CU), dissolution performance, and bioavailability of active pharmaceutical ingredients (API). Different particle engineering routes have been developed to prepare micron-sized API in a specific size range to deliver desirable biopharmaceutical performance. However, such API particles still risk varying bulk powder properties critical to successful manufacturing of quality drug products due to different particle shapes, size distribution, and surface energetics, arising from the anisotropy of API crystals. In this work, we systematically investigated key bulk properties of 10 different batches of Odanacatib prepared through either jet milling or fast precipitation, all of which meet the particle size specification established to ensure equivalent biopharmaceutical performance. However, they exhibited significantly different powder properties, solid-state properties, dissolution, and tablet CU. Among the 10 batches, a directly precipitated sample exhibited overall best performance, considering tabletability, dissolution, and CU. This work highlights the measurable impact of processing route on API properties and the importance of selecting a suitable processing route for preparing fine particles with optimal properties and performance. Full article
(This article belongs to the Special Issue Applications of Crystal Engineering in Drug Delivery)
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15 pages, 2262 KiB  
Article
Crystallization Thermodynamics of α-Lactose Monohydrate in Different Solvents
by Youliang Guan, Zujin Yang, Kui Wu and Hongbing Ji
Pharmaceutics 2022, 14(9), 1774; https://doi.org/10.3390/pharmaceutics14091774 - 25 Aug 2022
Cited by 2 | Viewed by 1609
Abstract
It is common to find that some of the lactose in dairy powders and pharmaceutical tablets is present in the unstable amorphous state. Therefore, their crystallization thermodynamics in different solvents are particularly important. In this paper, the solubility of α-lactose monohydrate (α-LM) in [...] Read more.
It is common to find that some of the lactose in dairy powders and pharmaceutical tablets is present in the unstable amorphous state. Therefore, their crystallization thermodynamics in different solvents are particularly important. In this paper, the solubility of α-lactose monohydrate (α-LM) in 15 mono-solvents such as ethanol, isopropanol, methanol, 1-propanol, 1-butanol, 2-butanol, isobutanol, 1-pentanol, isoamylol, 1-hexanol, 1-heptanol, 1-octanol, propanoic acid, acetonitrile, and cyclohexanone was evaluated by using the gravimetric method in the temperature ranges from 274.05 K to 323.05 K at constant pressure (1 atm). In the given temperature range, the solubility of α-LM in these solvents increased with the rising of temperature, the highest solubility of α-LM was found in methanol (2.37 × 104), and the lowest was found in 1-hexanol (0.80 × 105). In addition, the increase of α-LM solubility in isopropanol was the largest. The sequence at 298.15 K was: methanol > 1-butanol > isopropanol > ethanol > 1-propanol > 1-heptanol > isobutanol > propionic acid > 1-pentanol > 1-octanol > acetonitrile > isoamylol > 2-butanol > cyclohexanone > 1-hexanol. Solvent effect analysis shows that the properties of α-LM are more important than those of solvents. The Apelblat equation, λh equation, Wilson model, and NRTL model were used to correlate the experimental values. The root-mean-square deviation (RMSD) and relative average deviation (RAD) of all models were less than 2.68 × 10−2 and 1.41 × 10−6, respectively, implying that the fitted values of four thermodynamic models all agreed well with the experimental values. Moreover, the thermodynamic properties of the dissolution process (i.e., dissolution Gibbs free energy (ΔdisG), molar enthalpy (ΔdisH), and molar entropy (ΔdisS)) for α-LM in selected solvents were determined. The results indicate that ΔdisH/(J/mol) (from 0.2551 to 6.0575) and ΔdisS/(J/mol/K) (from 0.0010 to 0.0207) of α-LM in these solvents are all positive, and the values of ΔdisH and ΔdisS. ΔdisG/(J/mol) (from −0.0184 to −0.6380) are all negative. The values were observed to decrease with rising temperatures, implying that α-LM dissolution is an endothermic, entropy-driven, and spontaneous process. The solid–liquid equilibrium data and dissolution thermodynamics of α-LM were obtained, which provide a basis for industrial production. Full article
(This article belongs to the Special Issue Applications of Crystal Engineering in Drug Delivery)
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26 pages, 8510 KiB  
Article
Glasdegib Dimaleate: Synthesis, Characterization and Comparison of Its Properties with Monomaleate Analogue
by Boris Peklar, Franc Perdih, Damjan Makuc, Janez Plavec, Jérôme Cluzeau, Zoran Kitanovski and Zdenko Časar
Pharmaceutics 2022, 14(8), 1641; https://doi.org/10.3390/pharmaceutics14081641 - 6 Aug 2022
Cited by 1 | Viewed by 1873
Abstract
Glasdegib is a recently approved drug for the treatment of acute myeloid leukemia. It is formulated and marketed in monomaleate salt form. In our investigation, we were able to prepare a glasdegib dimaleate form, which could, in theory, exist in double-salt form or [...] Read more.
Glasdegib is a recently approved drug for the treatment of acute myeloid leukemia. It is formulated and marketed in monomaleate salt form. In our investigation, we were able to prepare a glasdegib dimaleate form, which could, in theory, exist in double-salt form or as a mixture of salt and co-crystal species. Therefore, the obtained crystals of glasdegib dimaleate were characterized via 15N ssNMR and single-crystal X-ray diffraction, which revealed that the obtained glasdegib dimaleate exists in double-salt form. This is a surprising finding based on the pKa values for glasdegib and maleic acid. Furthermore, we fully characterized the new dimaleate form using thermal analyses (DSC and TGA) and spectroscopy (IR and Raman). Finally, the physicochemical properties, such as solubility and chemical stability, of both forms were determined and compared. Full article
(This article belongs to the Special Issue Applications of Crystal Engineering in Drug Delivery)
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27 pages, 4336 KiB  
Article
Fabrication and Characterization of Tedizolid Phosphate Nanocrystals for Topical Ocular Application: Improved Solubilization and In Vitro Drug Release
by Mohd Abul Kalam, Muzaffar Iqbal, Abdullah Alshememry, Musaed Alkholief and Aws Alshamsan
Pharmaceutics 2022, 14(7), 1328; https://doi.org/10.3390/pharmaceutics14071328 - 23 Jun 2022
Cited by 8 | Viewed by 2111
Abstract
Positively charged NCs of TZP (0.1%, w/v) for ocular use were prepared by the antisolvent precipitation method. TZP is a novel 5-Hydroxymethyl-Oxazolidinone class of antibiotic and is effective against many drug-resistant bacterial infections. Even the phosphate salt of this drug [...] Read more.
Positively charged NCs of TZP (0.1%, w/v) for ocular use were prepared by the antisolvent precipitation method. TZP is a novel 5-Hydroxymethyl-Oxazolidinone class of antibiotic and is effective against many drug-resistant bacterial infections. Even the phosphate salt of this drug is poorly soluble, therefore the NCs were prepared for its better solubility and ocular availability. P188 was found better stabilizer than PVA for TZP-NCs. Characterization of the NCs including the particle-size, PDI, and ZP by Zeta-sizer, while morphology by SEM indicated that the preparation technique was successful to get the optimal sized (151.6 nm) TZP-NCs with good crystalline morphology. Mannitol (1%, w/v) prevented the crystal growth and provided good stabilization to NC1 during freeze-drying. FTIR spectroscopy confirmed the nano-crystallization did not alter the basic molecular structure of TZP. DSC and XRD studies indicated the reduced crystallinity of TZP-NC1, which potentiated its solubility. An increased solubility of TZP-NC1 (25.9 µgmL−1) as compared to pure TZP (18.4 µgmL−1) in STF with SLS. Addition of stearylamine (0.2%, w/v) and BKC (0.01%, w/v) have provided cationic (+29.4 mV) TZP-NCs. Redispersion of freeze-dried NCs in dextrose (5%, w/v) resulted in a clear transparent aqueous suspension of NC1 with osmolarity (298 mOsm·L−1) and viscosity (21.1 cps at 35 °C). Mannitol (cryoprotectant) during freeze-drying could also provide isotonicity to the nano-suspension at redispersion in dextrose solution. In vitro release in STF with SLS has shown relatively higher (78.8%) release of TZP from NC1 as compared to the conventional TZP-AqS (43.4%) at 12 h. TZP-NC1 was physically and chemically stable at three temperatures for 180 days. The above findings suggested that TZP-NC1 would be a promising alternative for ocular delivery of TZP with relatively improved performance. Full article
(This article belongs to the Special Issue Applications of Crystal Engineering in Drug Delivery)
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15 pages, 5375 KiB  
Article
Simultaneous Improvement of Dissolution Behavior and Oral Bioavailability of Antifungal Miconazole via Cocrystal and Salt Formation
by Ksenia V. Drozd, Alex N. Manin, Denis E. Boycov and German L. Perlovich
Pharmaceutics 2022, 14(5), 1107; https://doi.org/10.3390/pharmaceutics14051107 - 22 May 2022
Cited by 12 | Viewed by 2796
Abstract
Miconazole shows low oral bioavailability in humans due to poor aqueous solubility, although it has demonstrated various pharmacological activities such as antifungal, anti-tubercular and anti-tumor effects. Cocrystal/salt formation is one of the effective methods for solving this problem. In this study, different methods [...] Read more.
Miconazole shows low oral bioavailability in humans due to poor aqueous solubility, although it has demonstrated various pharmacological activities such as antifungal, anti-tubercular and anti-tumor effects. Cocrystal/salt formation is one of the effective methods for solving this problem. In this study, different methods (liquid-assisted grinding, slurrying and lyophilization) were used to investigate their impact on the formation of the miconazole multicomponent crystals with succinic, maleic and dl-tartaric acids. The solid state of the prepared powder was characterized by differential scanning calorimetry, powder X-ray diffraction and scanning electron microscopy. It was found that lyophilization not only promotes partial amorphization of both salts but also allows obtaining a new polymorph of the miconazole salt with dl-tartaric acid. The lyophilized salts compared with the same samples prepared by two other methods showed better dissolution rates but low stability during the studies due to rapid recrystallization. Overall, it was determined that the preparation method of multicomponent crystals affects the solid-state characteristics and miconazole physicochemical properties significantly. The in vivo studies revealed that the miconazole multicomponent crystals indicated the higher peak blood concentration and area under the curve from 0 to 32 h values 2.4-, 2.9- and 4.6-fold higher than the pure drug. Therefore, this study demonstrated that multicomponent crystals are promising formulations for enhancing the oral bioavailability of poorly soluble compounds. Full article
(This article belongs to the Special Issue Applications of Crystal Engineering in Drug Delivery)
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Review

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26 pages, 5676 KiB  
Review
Formulation Approaches to Crystalline Status Modification for Carotenoids: Impacts on Dissolution, Stability, Bioavailability, and Bioactivities
by Wan-Yi Liu, Yun-Shan Hsieh, Horng-Huey Ko and Yu-Tse Wu
Pharmaceutics 2023, 15(2), 485; https://doi.org/10.3390/pharmaceutics15020485 - 1 Feb 2023
Cited by 2 | Viewed by 1897
Abstract
Carotenoids, including carotenes and xanthophylls, have been identified as bioactive ingredients in foods and are considered to possess health-promoting effects. From a biopharmaceutical perspective, several physicochemical characteristics, such as scanty water solubility, restricted dissolution, and susceptibility to oxidation may influence their oral bioavailability [...] Read more.
Carotenoids, including carotenes and xanthophylls, have been identified as bioactive ingredients in foods and are considered to possess health-promoting effects. From a biopharmaceutical perspective, several physicochemical characteristics, such as scanty water solubility, restricted dissolution, and susceptibility to oxidation may influence their oral bioavailability and eventually, their effectiveness. In this review, we have summarized various formulation approaches that deal with the modification of crystalline status for carotenoids, which may improve their physicochemical properties, oral absorption, and biological effects. The mechanisms involving crystalline alteration and the typical methods for examining crystalline states in the pharmaceutical field have been included, and representative formulation approaches are introduced to unriddle the mechanisms and effects more clearly. Full article
(This article belongs to the Special Issue Applications of Crystal Engineering in Drug Delivery)
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49 pages, 1414 KiB  
Review
Mechanical Activation by Ball Milling as a Strategy to Prepare Highly Soluble Pharmaceutical Formulations in the Form of Co-Amorphous, Co-Crystals, or Polymorphs
by Luz María Martínez, Jorge Cruz-Angeles, Mónica Vázquez-Dávila, Eduardo Martínez, Paulina Cabada, Columba Navarrete-Bernal and Flor Cortez
Pharmaceutics 2022, 14(10), 2003; https://doi.org/10.3390/pharmaceutics14102003 - 21 Sep 2022
Cited by 15 | Viewed by 4181
Abstract
Almost half of orally administered active pharmaceutical ingredients (APIs) have low solubility, which affects their bioavailability. In the last two decades, several alternatives have been proposed to modify the crystalline structure of APIs to improve their solubility; these strategies consist of inducing supramolecular [...] Read more.
Almost half of orally administered active pharmaceutical ingredients (APIs) have low solubility, which affects their bioavailability. In the last two decades, several alternatives have been proposed to modify the crystalline structure of APIs to improve their solubility; these strategies consist of inducing supramolecular structural changes in the active pharmaceutical ingredients, such as the amorphization and preparation of co-crystals or polymorphs. Since many APIs are thermosensitive, non-thermal emerging alternative techniques, such as mechanical activation by milling, have become increasingly common as a preparation method for drug formulations. This review summarizes the recent research in preparing pharmaceutical formulations (co-amorphous, co-crystals, and polymorphs) through ball milling to enhance the physicochemical properties of active pharmaceutical ingredients. This report includes detailed experimental milling conditions (instrumentation, temperature, time, solvent, etc.), as well as solubility, bioavailability, structural, and thermal stability data. The results and description of characterization techniques to determine the structural modifications resulting from transforming a pure crystalline API into a co-crystal, polymorph, or co-amorphous system are presented. Additionally, the characterization methodologies and results of intermolecular interactions induced by mechanical activation are discussed to explain the properties of the pharmaceutical formulations obtained after the ball milling process. Full article
(This article belongs to the Special Issue Applications of Crystal Engineering in Drug Delivery)
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