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Stability and Formulation of Drug Substances and Pharmaceutical Products

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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 (31 October 2023) | Viewed by 12134

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Prof. Dr. Bernard Do

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Laboratoire et Matériaux et Santé, Université Paris-Saclay, 91400 Orsay, France
Interests: intrinsic stability; physico-chemical characterization; preformulation; structural elucidation; degradation pathways; drug development

Dr. Philippe-Henri Secretan

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Dear Colleagues,

From synthesis to administration, drug substances are regularly exposed to various physicochemical factors that may cause transformation. For instance, in the solid state, drug substances may be amenable to polymorphic change, solvate, and co-crystal formation. In solution, dissolved drug substances can degrade from exposure to natural light, solvolysis, and oxidation, among others. In pharmaceutical formulations, excipients may directly interact with the drug substance, inhibiting or inducing a transformation process. In these different contexts, the instability of the drug substance or its incompatibility with excipients can greatly affect both the efficacy and safety of therapy.

This Special Issue aims to draw together research in characterizing the transformation mechanisms of drug substances in a solid state, in solution, and in pharmaceutical formulations as well as their utilization to reduce drug substance degradation in the development of new, generic, or repurposed drug products.

Original research articles, short communications, and reviews on these topics are welcome.

Prof. Dr. Bernard Do
Dr. Philippe-Henri Secretan
Guest Editors

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Keywords

drug stability
solid state
stress testing
degradation pathways
structural elucidation
preformulation

Published Papers (9 papers)

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Research

13 pages, 1023 KiB

Open AccessArticle

Evaluation of the Stability of Newborn Hospital Parenteral Nutrition Solutions

by Luis Otero-Millán, Brais Bea-Mascato, Jose Luis Legido Soto, Noemi Martínez-López-De-Castro and Natividad Lago-Rivero

Pharmaceutics 2024, 16(3), 316; https://doi.org/10.3390/pharmaceutics16030316 - 23 Feb 2024

Cited by 2 | Viewed by 849

Abstract

(1) Background: parenteral nutrition (PN) solutions are an extremely complex mixture. It is composed of a multitude of chemical elements that can give rise to a large number of interactions that condition its stability and safety. The aim of this study was to evaluate the stability of PN solutions for preterm infants. (2) Methods: eight samples were prepared according to the protocol for prescribing PN in preterm infants. Samples PN1–PN7 had the normal progression of macronutrients and standard amounts of micronutrients for a 1 kg preterm infant. The PN8 sample had a high concentration of electrolytes, with the idea of forcing stability limits. Samples were stored both at room temperature and under refrigeration. Measurements of globule size, pH, density, and viscosity were performed in both storage protocols on different days after processing. (3) Results: the changes in the composition of the samples did not affect the evolution of the stability at the different measurement times and temperatures. Viscosity was affected by the compositional changes made in the PN samples, but no alterations due to time or temperature were observed. Density and pH remained stable, without significant changes due to time, storage temperature, or different composition. (4) Conclusion: all samples remained stable during the study period and did not undergo significant alterations due to compositional changes or different experimental conditions. Full article

(This article belongs to the Special Issue Stability and Formulation of Drug Substances and Pharmaceutical Products)

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21 pages, 4232 KiB

Open AccessArticle

Complex Spectroscopy Studies of Nifedipine Photodegradation

by Mirela Paraschiv, Monica Daescu, Cristina Bartha, Bogdan Chiricuta and Mihaela Baibarac

Pharmaceutics 2023, 15(11), 2613; https://doi.org/10.3390/pharmaceutics15112613 - 10 Nov 2023

Viewed by 917

Abstract

The aim of this work is to highlight the influence of UV light on the hydrolysis reaction of nifedipine (NIF) in the presence of alkaline solutions. In this context, the photodegradation of NIF in the absence of alkaline solutions caused (a) a change in the ratio between the absorbances of three bands in the UV-VIS spectra localized at 224–240 nm, 272–276 nm and 310–340 nm, assigned to the electronic transitions of -COOCH₃ groups, -NO₂ groups and a heterocycle with six atoms; (b) a red-shift of the photoluminescence (PL) band from 458 nm to 477 nm, simultaneous with an increase in its intensity; (c) a decrease in the ratio of the Raman line intensities, which peaked at 1224 cm⁻¹ and 1649 cm⁻¹, associated with the vibrational modes of -C-C-O in the ester group and C=C stretching; and (d) a decrease in the ratio between the absorbances of the IR bands, which peaked at 1493 cm⁻¹ and 1223 cm⁻¹, associated with the vibrational modes of the -NO₂ group and C-N stretching. These changes were explained considering the NIF photodegradation reaction, which leads to the generation of the compound 4-(2-nitrosophenyl)-2.6-dimethyl-3.5-dimethoxy carbonyl pyridine. The interaction of NIF with NaOH in the absence of UV light was demonstrated to induce changes in the vibrational mode of the -C-C-O bond in the ester group. The photodegradation of NIF after its reaction with NaOH induces significant changes highlighted in its (a) UV-VIS spectra, by the shift of the absorption band at 238 nm; (b) PL spectra, by the supraunitary value of the ratio between the emission band intensities at 394–396 nm and 450 nm; (c) Raman spectra, by the change in the ratio between the intensities of the lines that peaked at 1224 cm⁻¹ and 1649 cm⁻¹ from 0.61 to 0.49; and (d) FTIR spectra, by the lowered absorbance of the IR band at 1493 cm⁻¹ assigned to the vibrational mode of the -NO₂ group as a result of the generation of the nitroso compound. These changes were explained considering the hydrolysis reaction products of NIF, as the nitroso compound is converted to a lactam-type compound. The photodegradation reaction rate constants of NIF and NIF after interaction with NaOH were also reported. The decrease in thermal stability of NIF samples after interaction with NaOH, as well as of NIF after exposure to UV light compared to NIF prior to exposure to UV light, was demonstrated by thermogravimetry, and the key fragments were confirmed by mass spectrometry. Full article

(This article belongs to the Special Issue Stability and Formulation of Drug Substances and Pharmaceutical Products)

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18 pages, 6480 KiB

Open AccessArticle

Comprehensive Assessment of the Stability of Selected Coxibs in Variable Environmental Conditions along with the Assessment of Their Potential Hepatotoxicity

by Paweł Gumułka, Łukasz Pecio, Paweł Żmudzki, Krzesimir Ciura, Krystyna Skalicka-Woźniak, Monika Dąbrowska and Małgorzata Starek

Pharmaceutics 2023, 15(11), 2609; https://doi.org/10.3390/pharmaceutics15112609 - 9 Nov 2023

Viewed by 915

Abstract

Determining the influence of environmental factors on the stability of drugs is very helpful when choosing excipients, storage conditions or packaging materials. In addition, information about possible toxic degradation products enables detecting and avoiding the harmful side effects of the drug. We used the thin-layer chromatographic-densitometric procedure for the assay of five coxibs, conducted degradation studies in various environments and at different temperatures along with the determination of pharmacokinetic parameters. The results were subjected to chemometric analysis, to investigate and visualize the similarities and differences of the studied coxibs. Samples of the tested drug were also analyzed by UPLC-MS/MS in order to identify degradation products, and determine possible drug degradation pathways. Using the human liver cancer HepG2 cell line, the hepatotoxic effect of the degradation products was also determined. It was observed that all substances were relatively stable under the analyzed conditions and degraded more in acidic than alkaline environments. Robenacoxib is the drug that decomposes the fastest, and cimicoxib turned out to be the most stable. Robenacoxib also showed significant hepatotoxicity at the highest tested concentration, which correlates with the high degree of its degradation, and the probable formation of a more hepatoxic product. The obtained mass spectra of compounds formed as a result of hydrolysis of the protonated drug leading to the formation of several product ions, which enabled us to propose probable degradation pathways. Full article

(This article belongs to the Special Issue Stability and Formulation of Drug Substances and Pharmaceutical Products)

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14 pages, 2294 KiB

Open AccessArticle

Molecular Mechanisms Involved in the Chemical Instability of ONC201 and Methods to Counter Its Degradation in Solution

by Maxime Annereau, Marina Vignes, Lucas Denis, André Rieutord, François-Xavier Legrand, François Rioblanc, Muriel Paul, Jacques Grill, Philippe-Henri Secretan and Bernard Do

Pharmaceutics 2023, 15(10), 2371; https://doi.org/10.3390/pharmaceutics15102371 - 22 Sep 2023

Cited by 1 | Viewed by 1926

Abstract

Glioblastoma is one of the most common and aggressive forms of brain tumor, a rare disease for which there is a great need for innovative therapies. ONC201, a new drug substance, has been used in a compassionate treatment program where the choice of dosage form and regimen have yet to be justified. The prior knowledge needed to anticipate ONC201 stability problems has recently been partially addressed, by (i) showing that ONC201 is sensitive to light and oxidation and (ii) identifying the molecular structures of the main degradation products formed. The aim of the work presented here was to improve our understanding of the degradation pathways of ONC201 using data from ab initio calculations and experimental work to supplement the structural information we already published. The C–H bonds located αto the amine of the tetrahydropyridine group and those located alpha to the imine function of the dihydroimidazole group exhibit the lowest bond dissociation energies (BDEs) within the ONC201 molecule. Moreover, these values drop well below 90 kcal.mol⁻¹ when ONC201 is in an excited state (S1; T1). The structures of the photoproducts we had previously identified are consistent with these data, showing that they would have resulted from radical processes following the abstraction of alpha hydrogens. Concerning ONC201’s sensitivity to oxidation, the structures of the oxidation products matched the critical points revealed through mapped electrostatic potential (MEP) and average local ionization energy (ALIE). The data obtained from ab initio calculations and experimental work showed that the reactivity of ONC201 to light and oxidation conditions is highly dependent on pH. While an acidic environment (pH < 6) contributes to making ONC201 quantitatively more stable in solution in the face of oxidation and photo-oxidation, it nevertheless seems that certain chemical groups in the molecule are more exposed to nucleophilic attacks, which explains the variation observed in the profile of degradation products formed in the presence of certain antioxidants tested. This information is crucial to better understand the stability results in the presence of antioxidant agents and to determine the right conditions for them to act. Full article

(This article belongs to the Special Issue Stability and Formulation of Drug Substances and Pharmaceutical Products)

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12 pages, 2460 KiB

Open AccessArticle

Stability Study of Fosfomycin in Elastomeric Pumps at 4 °C and 34 °C: Technical Bases for a Continuous Infusion Use for Outpatient Parenteral Antibiotic Therapy

by Alessandra Manca, Alice Palermiti, Jacopo Mula, Jessica Cusato, Domenico Maiese, Marco Simiele, Amedeo De Nicolò and Antonio D’Avolio

Pharmaceutics 2023, 15(9), 2347; https://doi.org/10.3390/pharmaceutics15092347 - 19 Sep 2023

Viewed by 1400

Abstract

Background: Fosfomycin acts against aerobic Gram−/+ bacteria by blocking the synthesis of peptidoglycan. Its use has been currently re-evaluated for intravenous administration for the treatment of systemic infections by multidrug-resistant bacteria. Concentration-/time-dependent activity has been suggested, with potential clinical advantages from prolonged or continuous infusion. Nevertheless, little is known about Fosfomycin stability in elastomeric pumps. The aim of the present work was stability investigation before administration at 4 °C and during administration at 34 °C. Methods: InfectoFos^® (InfectoPharm s.r.l., Milan, Italy) preparation for intravenous use in elastomeric pumps at 4 °C and 34 °C was analyzed following EMA guidelines for drug stability. Samples were analyzed with an ultra-high performance liquid chromatography coupled with tandem mass spectrometry method on a LX50^® UHPLC system equipped with a QSight 220^® (Perkin Elmer, Milan, Italy) tandem mass spectrometer. Results: Fosfomycin in elastomeric preparation is stable for at least 5 days at a storage temperature of 4 °C and 34 °C. Conclusions: The results suggest Fosfomycin eligibility for continuous infusion even in the context of outpatient parenteral antibiotic therapy. Therefore, this approach should be tested in clinical and pharmacokinetic studies, in order to evaluate the possible gains in the pharmacokinetic profile and the clinical effectiveness. Full article

(This article belongs to the Special Issue Stability and Formulation of Drug Substances and Pharmaceutical Products)

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17 pages, 1841 KiB

Open AccessArticle

Novel Bioequivalent Tablet of Solifenacin Succinate Prepared Using Direct Compression Technique for Improved Chemical Stability

by Do Hwan Kim, Myoung Jin Ho, Chan Kyu Jeong and Myung Joo Kang

Pharmaceutics 2023, 15(6), 1723; https://doi.org/10.3390/pharmaceutics15061723 - 14 Jun 2023

Viewed by 1346

Abstract

We designed a bioequivalent tablet form of solifenacin succinate (SOL) with an improved storage stability using a direct compression (DC) technique. An optimal direct compressed tablet (DCT) containing an active substance (10 mg), lactose monohydrate, and silicified microcrystalline cellulose as diluents, crospovidone as a disintegrant, and hydrophilic fumed silica as an anti-coning agent was constructed by evaluating the drug content uniformity, mechanical properties, and in vitro dissolution. The physicochemical and mechanical properties of the DCT were as follows: drug content 100.1 ± 0.7%, disintegration time of 6.7 min, over 95% release within 30 min in dissolution media (pH 1.2, 4.0, 6.8, and distilled water), hardness > 107.8 N, and friability ~0.11%. The SOL-loaded tablet fabricated via DC showed an improved stability at 40 °C and RH 75%, exhibiting markedly reduced degradation products compared to those fabricated using ethanol or water-based wet granulation or a marketed product (Vesicare^®, Astellas Pharma). Moreover, in a bioequivalence study in healthy subjects (n = 24), the optimized DCT offered a pharmacokinetic profile comparable to that of the marketed product, with no statistical differences in the pharmacokinetic parameters. The 90% CIs for the geometric mean ratios of the test to the reference formulation for the area under the curve and the maximum drug concentration in plasma were 0.98–1.05 and 0.98–1.07, respectively, and satisfied the FDA regulatory criteria for bioequivalence. Thus, we conclude that DCT is a beneficial oral dosage form of SOL with an improved chemical stability. Full article

(This article belongs to the Special Issue Stability and Formulation of Drug Substances and Pharmaceutical Products)

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17 pages, 3177 KiB

Open AccessArticle

The Phase Diagram of the API Benzocaine and Its Highly Persistent, Metastable Crystalline Polymorphs

by Ivo B. Rietveld, Hiroshi Akiba, Osamu Yamamuro, Maria Barrio, René Céolin and Josep-Lluís Tamarit

Pharmaceutics 2023, 15(5), 1549; https://doi.org/10.3390/pharmaceutics15051549 - 20 May 2023

Cited by 1 | Viewed by 1232

Abstract

The availability of sufficient amounts of form I of benzocaine has led to the investigation of its phase relationships with the other two existing forms, II and III, using adiabatic calorimetry, powder X-ray diffraction, and high-pressure differential thermal analysis. The latter two forms were known to have an enantiotropic phase relationship in which form III is stable at low-temperatures and high-pressures, while form II is stable at room temperature with respect to form III. Using adiabatic calorimetry data, it can be concluded, that form I is the stable low-temperature, high-pressure form, which also happens to be the most stable form at room temperature; however, due to its persistence at room temperature, form II is still the most convenient polymorph to use in formulations. Form III presents a case of overall monotropy and does not possess any stability domain in the pressure–temperature phase diagram. Heat capacity data for benzocaine have been obtained by adiabatic calorimetry from 11 K to 369 K above its melting point, which can be used to compare to results from in silico crystal structure prediction. Full article

(This article belongs to the Special Issue Stability and Formulation of Drug Substances and Pharmaceutical Products)

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18 pages, 9174 KiB

Open AccessArticle

Supramolecular Arrangement of Doxycycline with Sulfobutylether-β-Cyclodextrin: Impact on Nanostructuration with Chitosan, Drug Degradation and Antimicrobial Potency

by Renata Carvalho Feitosa, Juliana Souza Ribeiro Costa, Marcelo van Vliet Lima, Elina Sawa Akioka Ishikawa, Karina Cogo Müller, Fernando Bonin Okasaki, Edvaldo Sabadini, Claudia Garnero, Marcela Raquel Longhi, Vladimir Lavayen, Arnóbio Antônio da Silva-Júnior and Laura Oliveira-Nascimento

Pharmaceutics 2023, 15(4), 1285; https://doi.org/10.3390/pharmaceutics15041285 - 19 Apr 2023

Cited by 1 | Viewed by 1309

Abstract

Doxycycline (DX) is a well-established and broad-spectrum antimicrobial drug. However, DX has drawbacks, such as physicochemical instability in aqueous media and bacterial resistance. The inclusion of drugs in cyclodextrin complexes and their loading into nanocarriers can overcome these limitations. Thus, we studied the DX/sulfobutylether-β-CD (SBE-β-CD) inclusion complex for the first time and used it to reticulate chitosan. The resulting particles were evaluated by their physicochemical characteristics and antibacterial activity. DX/SBE-β-CD complexes were characterized by nuclear magnetic resonance, infrared spectroscopy, thermal analysis, X-ray diffraction, and scanning electron microscopy (SEM), whereas DX-loaded nanoparticles were characterized by dynamic light scattering, SEM, and drug content. The partial inclusion of the DX molecule in CD happened in a 1:1 proportion and brought increased stability to solid DX upon thermal degradation. Chitosan-complex nanoparticles measured approximately 200 nm, with a narrow polydispersity and particles with sufficient drug encapsulation for microbiological studies. Both formulations preserved the antimicrobial activity of DX against Staphylococcus aureus, whereas DX/SBE-β-CD inclusion complexes were also active against Klebsiella pneumoniae, indicating the potential use of these formulations as drug delivery systems to treat local infections. Full article

(This article belongs to the Special Issue Stability and Formulation of Drug Substances and Pharmaceutical Products)

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18 pages, 1789 KiB

Open AccessArticle

Hospital Production of Sterile 2% Propofol Nanoemulsion: Proof of Concept

by Amélie Cèbe, Bérangère Dessane, Pauline Gohier, Jean-Marc Bernadou, Arnaud Venet, Fabien Xuereb and Sylvie Crauste-Manciet

Pharmaceutics 2023, 15(3), 905; https://doi.org/10.3390/pharmaceutics15030905 - 10 Mar 2023

Cited by 1 | Viewed by 1500

Abstract

In the context of essential drug shortages, this article reports a proof of concept for the hospital preparation of a 2% propofol injectable nanoemulsion. Two processes for propofol were assessed: mixing propofol with the commercial Intralipid^® 20% emulsion and a “de novo” process performed using separate raw materials (i.e., oil, water, and surfactant) and optimized for droplet size reduction with a high-pressure homogenizer. A propofol HPLC-UV stability-indicating method was developed for process validation and short-term stability. In addition, free propofol in the aqueous phase was quantified by dialysis. To envision routine production, sterility and endotoxin tests were validated. Only the “de novo” process using high-pressure homogenization gave satisfactory physical results similar to commercialized Diprivan^® 2%. Both terminal heat sterilization processes (121 °C, 15 min and 0.22 µm filtration) were validated, but an additional pH adjustment was required prior to heat sterilization. The propofol nanoemulsion was monodisperse with a 160 nm mean droplet size, and no droplets were larger than 5µm. We confirmed that free propofol in the aqueous phase of the emulsion was similar to Diprivan 2%, and the chemical stability of propofol was validated. In conclusion, the proof of concept for the in-house 2% propofol nanoemulsion preparation was successfully demonstrated, opening the field for the possible production of the nanoemulsion in hospital pharmacies. Full article

(This article belongs to the Special Issue Stability and Formulation of Drug Substances and Pharmaceutical Products)

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